Copper Catalyzed C-N Cross-Coupling Reaction of Aryl Boronic Acids at Room Temperature through Chelation Assistance

Article abstract of DOI:10.1021/acs.joc.7b00002

A copper-catalyzed selective C-N cross-coupling has been developed based on chelation-assisted amidation of readily available aryl boronic acids at room-temperature under open-flask conditions. The reaction is scalable and tolerates a wide spectrum of functional groups delivering fully substituted unsymmetrical amides in high yields (up to 96%). The C-N cross coupling also established with aryl silanes, extending the palette of coupling partners of this strategy.

Full text of DOI:10.1021/acs.joc.7b00002

Subscriber access provided by University of Colorado Boulder
Note
Copper Catalyzed C–N Cross-Coupling Reaction of Aryl Boronic
Acids at Room Temperature through Chelation Assistance
Harekrishna Sahoo, Sayan Mukherjee, Gowri Sankar Grandhi, Jayaraman Selvakumar, and Mahiuddin Baidya
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00002 • Publication Date (Web): 10 Feb 2017
Downloaded from http://pubs.acs.org on February 10, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 9
The Journal of Organic Chemistry
1
2
3
4
5
6
Copper Catalyzed C–N Cross-Coupling Reaction of Aryl Boronic
Acids at Room Temperature through Chelation Assistance
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Harekrishna Sahoo, Sayan Mukherjee, Gowri Sankar Grandhi, Jayaraman Selvakumar, and Mahiuddin
Baidya*
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, Tamil Nadu, India
ABSTRACT: A copperꢀcatalyzed selective C–N crossꢀcoupling has been developed based on chelationꢀassisted amidation of
readily available aryl boronic acids at roomꢀtemperature under openꢀflask conditions. The reaction is scalable and tolerates a wide
spectrum of functional groups delivering fully susbtituted unsymmetrical amides in high yields (up to 96%). The C–N cross
coupling also established with aryl silanes, extending the palette of coupling partners of this strategy.
amides. However, they are not amenable to aryl substituted
tertiary amides.
Fully substituted amides, particularly unsymmetrical systems
possessing a (hetero)aryl substituent, represent a pivotal strucꢀ
tural motif of many natural products and pharmaceuticals with
11
Recently, chelationꢀcontrolled transitionꢀmetal catalysis has
emerged as a powerful tool for selective organic transforꢀ
mation and has been successfully implemented for the con
1
diverse biological activities (Figure 1). They also have signifꢀ
icant applications to functional materials and synthesis of difꢀ
2
ferent heterocyclic frameworks. Consequently, the developꢀ
ment of mild and efficient synthetic routes toward this scaffold
is of utmost importance.
Scheme 1. Copper catalyzed chelation assisted selective C–N
bond formation at ambient temperature promoted by a removꢀ
able, bidentate auxiliary.
Figure 1: Selected examples of bioactive compounds having
Nꢀarylated amide linkage.
1
2ꢀ14
struction of various C–N bonds.
Furthermore, this strategy
Traditionally, amides have been prepared by the reaction of
also provides a platform to execute previously unattainable
reactions with more abundant and less expensive firstꢀrow
transition metals. We envisaged that incorporation of a cheꢀ
lating group in the form of an amide framework could promote
the Nꢀarylation with firstꢀrow transition metals and thus, fully
substituted amides with unsymmetrical substitution patterns
could be realized under mild conditions. However, a decisive
choice of catalytic system is necessary to nullify the competꢀ
3
4
amines with carboxylic acid derivatives, aldehydes, alcoꢀ
5
6
hols, or hydration of nitriles, and hydroamination of alꢀ
13
7
kynes . However, adaptation of these protocols for the syntheꢀ
sis of the aforementioned amides is usually plagued. The situaꢀ
tion becomes adverse when multiple reaction sites are present.
A straightforward route could be direct Nꢀarylation of amides,
8
9
and the BuchwaldꢀHartwig and ChanꢀLam reactions are two
related methods that are widely practiced for this purpose.
While the pioneering works by Buchwald and Hartwig deꢀ
scribed a number of methods for the synthesis of amides and
related compounds based on palladiumꢀcatalyzed amidation of
aryl halides, requirements of precious palladium catalysts and
phosphine ligands make this method expensive. On the other
hand, copperꢀmediated oxidative amination of aryl boronic
acids, the so called ChanꢀLam reaction, is costꢀeffective; howꢀ
ever, when this protocol was employed for the amide derivaꢀ
tives, the N,Nꢀdisubstituted amide products were obtained in
14
ing C–H bond functionalization pitfall of amides. Toward
this end, Nicholls’s group reported an intriguing copper cataꢀ
lyzed amidation of aryl bromides using 8ꢀamidoquinolines,
15
albeit at elevated temperature. Herein, we report an unpreceꢀ
dented copperꢀcatalyzed picolinamideꢀassisted C–N crossꢀ
coupling with readily available boronic acids en route to unꢀ
symmetrical tertiary amides at room temperature under openꢀ
flask conditions (Scheme 1). In addition, we have also sucꢀ
cessfully demonstrated Nꢀarylation with aryl silanes, extendꢀ
ing the palette of coupling partners for this strategy.
9
b
poor yields. Furthermore, various metalꢀcatalyzed protocols
such as transamidation, alkylation of primary amides, and
We commenced our investigation by studying the reaction of
picolinamide 1a with phenylboronic acid 2a (Scheme 2). After
judicious evaluation of reaction parameters, we identified that
10
acylation of amines with ester have also been established. All
these protocols are very general for the synthesis of secondary
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 9
16
a protocol based on Cu(OAc) ⋅H O, DMAP, and KI in 1,2ꢀ
deficient groups furnished the Nꢀarylated products 3baꢀ3ma in
2
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
good to excellent yield (54ꢀ93%). Various functional groups,
such as methoxy (3da, 3ka), chloro (3ea), ester (3fa), ketone
(3ga), cyano (3ha), trifluoromethyl (3ia), and nitro (3ja) can
be accommodated. Notably, nitrogenꢀcontaining heterocycles
posed no problem, affording 3na in 66% yield. The picoꢀ
linamides having benzyl (3oa-pa) and tethered aliphatic
amines (3qa-ra) also produced the corresponding products in
very high yield. We were pleased to find that cyclopropyl
(3ta) and allyl (3ua) residues were unaffected, demonstrating
the mildness of the reaction conditions. Interestingly, the cataꢀ
lytic system boded well with the tryptamine derived picoꢀ
linamide (1v). Although an unprotected nucleophilic nitrogen
center is present at the indole moiety, C–N crossꢀcoupling
selectively took place at the amideꢀnitrogen, delivering 3va in
dimethoxy ethane (DME) at room temperature in the presence
of air (openꢀflask) delivered 3aa in 96% isolated yield (see SI
for optimization details). The structure of 3aa was unambiguꢀ
1
7
ously established by Xꢀray analysis. Interestingly, the ortho
C–H arylation was not observed under this conditions. In genꢀ
eral, the reaction is more fruitful in the presence of organic
bases than inorganic bases. The catalytic system is also effecꢀ
tive with silver oxidants; however, a higher temperature of 80
o
C was necessary. The reaction completely shuts down in the
absence of copper catalyst and is also not productive in the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
presence
of
Co(OAc) ⋅4H O,
Ni(OAc) ⋅4H O,
or
2
2
2
2
Fe(NO ) ⋅9H O catalysts.
3
3
2
Scheme 2. Copperꢀcatalyzed chelationꢀassisted selective C–N
crossꢀcoupling.
9
0% yield. This result not only highlights the exquisite
chemoselectivity of our protocol but also established the imꢀ
portance of chelation for this transformation.
Next, the adaptability of this copper catalysis was examined
with a series of commercially available boronic acids 2bꢀj
(Table 2). As shown, the preparative scope was rather genꢀ
eral regardless of whether electronꢀdonating or electronꢀ
withdrawing groups were present or not, producing desired
product in high yields (up to 91%). Remarkably, a variety of
aryl halides (4acꢀae, 4ai, 4ud, and 4vd), nitrile (4af and 4vj),
aldehydes (4ag and 4aj), and heterocycles (4ak, 4vdꢀvj) are
effective. Importantly, even a boronic acid containing free
hydroxyl group could be employed as a coupling partner, givꢀ
ing 4ah in 55% yield.
Prompted by these results, we sought to explore the chelaꢀ
tion assisted C–N crossꢀcoupling reaction for various substiꢀ
tuted amides 1 (Table 1). The reaction is quite general, and the
picolinamides having both electronꢀrich as well as electronꢀ
Table 1. Substrates scope of copper-catalyzed chelation-
a
assisted C–N cross-coupling reaction.
To extend the reaction scope further, we set out searching
for other heterocycleꢀsubstituted amides and aryl coupling
partners in a permutation way. Gratifyingly, we found that the
Cu(OAc)2.H2O (20 mol %)
DMAP (20 mol %)
KI (20 mol %)
O
HO
OH
O
B
R
R
N
N
H
+
N
3
N
DME, rt, air, 36 h
1
2a
Table 2. Scope of aryl boronic acids for C–N cross-
a
coupling reaction.
N
N
N
N
O
O
F3C
3
ba, 88%
ia, 90%b
3
Crystal structure of 3aa
X = Me, 3ca (86%)
OMe, 3da (90%)b
Cl, 3ea (88%)b
N
N
X
N
CO2Me, 3fa (54%)
N
COMe, 3ga (77%)b
O
O
CN, 3ha (85%)
X
X = NO , 3ja (83%)
2
OMe, 3ka (90%)
N
N
Me
N
N
N
N
O
O
Br
N
O
Me
Me
3
la, 75%
3ma, 93%
3na, 66%
R
N
N
N
R
N
O
N
N
O
O
MeO
R = H, 3oa (73%)
F, 3pa (89%)
3sa, 89%
R = H, 3qa (67%)
OMe, 3ra (90%), gram scale
N
N
N
N
N
N
O
HN
O
O
3
ta, 55%
3ua, 85%
3va, (90%), (x-ray)
a
Conditions: 1 (0.2 mmol), 2 (2.5 equiv), Cu(OAc) ˑH O (20 mol
2
2
a
%), KI (20 mol %), DMAP (20 mol %), DME (1.5 mL), rt, air,
and 36 h. Yields are isolated quantities. DMAP: 4ꢀ
Dimethylaminopyridine.
Conditions: 1 (0.2 mmol), 2a (2.5 equiv), Cu(OAc) ˑH O (20 mol
2
2
%
), KI (20 mol %), DMAP (20 mol %), DME (1.5 mL), rt, air,
b
and 36 h. Yields are isolated quantities. Reaction time was 48 h.
2
ACS Paragon Plus Environment

Page 3 of 9
The Journal of Organic Chemistry
such as TEMPO, and butylated hydroxytoluene (BHT), a sigꢀ
reaction of amide 5a derived from (2ꢀaminophenyl)pyrazole
14f
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(2ꢀAPP) and aryl silane 6 was fruitful, and the tertiary amide
5aa was obtained in 97% yield, albeit a modified reaction
conditions was necessary (Table 3, for details optimization,
see SI, page S6). Other 2ꢀAPPꢀsubstituted amides have also
efficiently participated in this reaction, delivering 5baꢀfa in
excellent yields. Furthermore, this C–N crossꢀcoupling reacꢀ
tion under the modified conditions was also effective with
aminophenyloxazoline (7aa, 94% yield). However, the reacꢀ
tions of picolinamide substrates failed miserably with the reꢀ
covery of respective starting materials. Furthermore, the amide
nificant amount of product 3aa was isolated (Scheme 5a).
These results refute the involvement of radical species in the
reaction pathway. To investigate the electronic effects on the
chelated complex, we have performed a parallel experiment
with a 1:1 mixture of substrates 1c and 1g under standard conꢀ
dition (Scheme 5b). We have observed that the reaction of
electron rich substrate 1c proceeded much faster compared to
that of electron poor substrate 1g.
1
3c
Although comprehensive mechanistic details must await
further investigation, based on the preceding discussion and
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
a also reacts with boronic acid 2a and a moderate yield was
18
literature survey a plausible reaction mechanism was depictꢀ
obtained at elevated temperature (Scheme 3). Tentatively, the
dissimilarity in ringꢀsize of metal complexes is responsible for
different trends in reactivity.
ed in Scheme 5c. After complexation of 1 with copper cataꢀ
lyst, Cu(II)cyclometalated species A is formed, which on
transmetallation with PhB(OH)2 produces the complex B.
Next, disproportionation reaction or oxidation with air yields
Table 3. Exploration of chelation-controlled C-N cross-
18bꢀd
a
higher oxidation Cu(III) complex C,
which undergoes
coupling reaction with aryl silane
smooth reductive elimination to deliver the product 3 with
concurrent formation of low valent Cu(I) species. Finally, the
low valent copper species converts to active catalyst Cu(II)
with air as a terminal oxidant to continue the catalytic cycle.
Scheme 4. Gramꢀscale synthesis, sequential Nꢀarylation, and
removal of the auxiliary.
a
Conditions: 5a (0.2 mmol), 8 (3 equiv), Cu(OAc) (30 mol %),
2
o
Ag O (1 equiv), AgF (25 mol %), DMSO (1.5 mL), 80 C, O , 24
2
2
h. Yields are isolated quantities.
Scheme 5. Control experiments (a, b) and plausible reaction
mechanism (c).
Scheme 3. Reaction of 5a with phenyl boronic acid.
To highlight the synthetic utility of the present protocol, a
gramꢀscale reaction with substrate 1v was performed (Scheme
4
) and the efficiency of the smallꢀscale reaction was retained
upon scaleꢀup, delivering 3va in 82% yield. The chemoselecꢀ
tive installation of aryl functionality allowed us sequential Nꢀ
arylation of the tryptamine moiety with ease and thus, tryptaꢀ
mine derivatives (8,9) with tunable substitutions patterns were
synthesized in 91% and 59% yields with 4ꢀiodoanisole and 2ꢀ
iodothiophene, respectively, in the presence of catalytic copꢀ
per iodide (Scheme 4). Furthermore, the picolinamide auxiliaꢀ
ry can be easily cleaved under mild conditions to afford the
free amine 10 in excellent yield.
To probe the reaction mechanism, various control experiꢀ
ments were considered (Scheme 5). The reaction was unfruitꢀ
ful for substrates 1a’ with the recovery of starting material,
suggesting that the chelation with the picolinamide is crucial
(Scheme 5a). Further, in the presence of radical scavengers
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 9
In conclusion, we have developed a copperꢀcatalyzed, pracꢀ
and the mixture was allowed to stir at room temperature for
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
tical C–N crossꢀcoupling reaction based on chelation assisted
amidation of readily available boronic acids. The protocol is
operationally simple, chemoselective, scalable, and tolerates a
wide range of functional groups, delivering fully substituted
unsymmetrical amides in very high yields (up to 96%). The
scope of the coupling protocol was further extended using 1ꢀ
36 h. After completion of the reaction (TLC monitored), it
was transferred to a round bottom flask after dilution with
CH Cl and extracted with saturated NaHCO solution. The
2
2
3
organic layer was dried with Na SO and the solvent was
2
4
evaporated under reduced pressure and the resulting residue
was purified by column chromatography on silica gel
with a gradient eluent of hexane and ethyl acetate to
give tertiary amides 3/4.
(
2ꢀaminophenyl)pyrazole and aminophenyloxazoline bidentate
auxiliaries in combination with aryl silanes. Further investigaꢀ
tions on the reaction mechanism and application of this strateꢀ
gy in the synthesis of bioactive compounds are currently being
pursued in our laboratory.
N,N-diphenylpicolinamide (3aa): white solid (53 mg, 96%),
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Mp: (125ꢀ127 °C). H NMR (500 MHz, CDCl ): δ = 8.32 (dt,
3
1
2
J = 5.00 Hz, J = 1.10 Hz, 1H), 7.67ꢀ7.62 (m, 2H), 7.27ꢀ7.14
(m, 11H); C NMR (125 MHz, CDCl ): δ = 168.8, 154.5,
1
3
3
148.5, 143.4, 136.5, 129.1, 127.4, 126.5, 124.3, 124.2; HRMS
(ESI/TOFꢀQ) m/z: [M + H]+ Calcd for C H N OH 275.1184;
EXPERIMENTAL SECTION:
18
14
2
General Information: All nonꢀaqueous reactions were carried
out under an atmosphere of nitrogen in flameꢀdried glassware
and were stirred using a magnetic stir plate. All reactions were
carried out using anhydrous solvent unless otherwise noted.
DCE and PhCl were dried over calcium hydride. Dry toluene
and DME were prepared by distilling over sodium ketyl.
Cu(OAc) ·H O, CuCl, Cu(OAc) , and CuBr were purchased
Found 275.1201.
N-(naphthalen-2-yl)-N-phenylpicolinamide (3ba): pale brown
o
1
solid (57 mg, 88%), Mp (130ꢀ132 C). H NMR (500 MHz,
CDCl ): δ = 8.25ꢀ8.18 (m, 2H), 7.84ꢀ7.77 (m, 2H), 7.52ꢀ7.12
3
1
3
(m, 12H); C NMR (125 MHz, CDCl ): δ = 168.9, 153.9,
3
148.0, 138.9, 135.8, 134.0, 130.0, 128.4, 127.9 (2×C), 126.7,
125.9, 125.5, 125.0, 123.8, 122.9; HRMS (ESI/TOFꢀQ) m/z:
[M + H]+ Calcd for C H N OH 325.1341; Found 325.1358.
2
2
2
2
from Alfa Asear Company.All reactions were monitored by
thin layer chromatography (TLC) on WhatmanPartisil® K6F
TLC plates (silica gel 60 Å, 0.25 mm thickness) and visualized
using a UV lamp (366 or 254 nm) or by use of one of the folꢀ
lowing visualization reagents: PMA: 10 g phosphomolybdic
22
16
2
N-phenyl-N-(p-tolyl)picolinamide (3ca): white solid (50 mg,
o
1
88%), Mp (109ꢀ111 C). H NMR (500 MHz, CDCl
8.34 (d, J = 4.70 Hz, 1H), 7.66ꢀ7.60 (m, 2H), 7.25ꢀ7.07 (m,
): δ =
3
1
3
acid/ 100 mL ethanol, KMnO : 0.75 g potassium permangaꢀ
10H), 2.29 (s, 3H); C NMR (125 MHz, CDCl3): δ = 168.8,
154.6, 148.5, 143.4, 140.7, 136.4, 129.7, 129.0, 127.2, 126.3,
124.2, 124.1, 21.0; ; HRMS (ESI/TOFꢀQ) m/z: [M + H]+
4
nate, 5 g K CO , / 100mL water. Products were isolated by
2
3
column chromatography (Merck silica gel 100ꢀ200ꢁm). Yields
refer to chromatographically and spectroscopically homogeꢀ
Calcd for C19
H N ONa 311.1160; Found 311.1156.
16 2
1
3
1
nous materials unless noted otherwise. C and H NMR specꢀ
tra were recorded on a Bruker 400 or Bruker 500 MHz specꢀ
trometers. Chemical shift values (δ) are reported in ppm and
N-(4-methoxyphenyl)-N-phenylpicolinamide (3da): white solid
o
1
(55 mg, 90%), Mp (137ꢀ139 C). H NMR (400 MHz, CDCl ):
3
calibrated to the residual solvent peak CDCl δ = 7.2600 ppm
δ = 8.35 (d, J = 4.76 Hz, 1H), 7.67ꢀ7.59 (m, 2H), 7.16ꢀ7.13
3
1
13
1
13
for H, δ = 77.16 for C and MeOHꢀd δ = 3.3100 ppm for H;
δ = 49.15 for C or calibrated to tetramethylsilane (δ = 0.00).
All NMR spectra were recorded at ambient temperature (290
(m, 8H), 6.80 (s, 2H), 3.76 (s, 3H); C NMR (125 MHz,
4
13
CDCl
): δ = 168.5, 157.7, 154.3, 148.2, 143.2, 136.1, 135.8,
3
128.6, 128.4, 126.6, 125.9, 123.8, 123.7, 114.0, 55.1; HRMS
1
K) unless otherwise noted. H NMR spectra are reported as
(ESI/TOFꢀQ) m/z: [M + Na]+ Calcd for C19
327.1109; Found 327.1105.
H N O Na
16 2 2
follows: chemical shift (multiplicity, coupling constant, inteꢀ
gration). The following abbreviations are used to indicate mulꢀ
tiplicities: s, singlet; d, doublet; t, triplet; q, quartet; quint,
quintet, sext, sextet, sept, septet, m, multiplet; dd, doublet of
doublet; dt, doublet of triplet; dq, doublet of quartet; td, triplet
of doublet; tt, triplet of triplet; dq, doublet of quartet; br,
broad; app, apparent. Mass spectra were recorded by electron
spray ionization (ESI) method on a QꢀTOF Micro with lock
spray source. The crystal data were collected and integrated
using a BrukerAxs kappa apex2 CCD diffractometer, with
graphite monochromated MoꢀKα radiation.
N-(4-chlorophenyl)-N-phenylpicolinamide (3ea): pale yellow
o
1
solid (54 mg, 88%), Mp (118ꢀ120 C). H NMR (500 MHz,
CDCl ): δ = 8.32 (d, J = 4.20 Hz, 1H), 7.69ꢀ7.66 (m, 2H),
3
13
7
1
1
.25ꢀ7.13 (m, 10H); C NMR (125 MHz, CDCl ): δ = 168.5,
3
53.8, 148.3, 142.8, 141.8, 136.4, 131.8, 129.0, 128.2, 127.2,
26.6, 124.3 124.1; HRMS (ESI/TOFꢀQ) m/z: [M + Na]+
Calcd for C H ClN ONa 331.0614; Found 331.0627.
18 13
2
methyl 4-(N-phenylpicolinamido)benzoate (3fa): white solid
o
1
(
36 mg, 52%), Mp (107ꢀ109 C). H NMR (500 MHz, CDCl ):
1
9
3
The picolinamides 1 and (2ꢀAminophenyl)pyrazole based
δ = 8.31 (d, J = 4.30 Hz, 1H), 7.94 (d, J = 8.35 Hz, 2H), 7.69
d, J = 4.05 Hz, 2H), 7.29 (t, J = 7.47 Hz, 2H), 7.22ꢀ7.15 (m,
2
0
carboxamide derivatives 5a were synthesized following preꢀ
viously published procedures. The aryl boronic acid derivaꢀ
tives 2 were purchased from Spectrochem Company.
(
6
13
H), 3.88 (s, 3H); C NMR (125 MHz, CDCl ): δ = 166.5,
3
164.2, 151.6, 146.2, 155.3, 140.5, 134.4, 128.2, 127.0, 125.4,
25.3, 124.7, 124.3, 122.4, 122.2, 50.0; HRMS (ESI/TOFꢀQ)
m/z: [M + Na]+ Calcd for C H N O Na 355.1059;
General procedure for the copper catalysed C–N cross-
coupling of boronic acids: The picolinamides 1 (0.20 mmol),
1
20
16
2
3
aryl boronic acid derivatives
2
(0.50 mmol),
Cu(OAc) ·H O (20 mol %), DMAP (20 mol %), and KI
N-(4-acetylphenyl)-N-phenylpicolinamide (3ga): white solid
2
2
o
1
(
20 mol %) were taken in a dried schlenk tube with a magꢀ
netic stir. Then DME (1.5 mL) was added with a syringe
(49mg, 66%), Mp (124ꢀ126 C). H NMR (500 MHz, CDCl ):
3
δ = 8.31 (d, J = 4.70 Hz, 1H), 7.87 (d, J = 8.55 Hz, 2H), 7.71ꢀ
4
ACS Paragon Plus Environment

Page 5 of 9
The Journal of Organic Chemistry
7
.69 (m, 2H), 7.29 (t, J = 7.70 Hz, 2H), 7.26ꢀ7.21 (m, 4H), HRMS (ESI/TOFꢀQ) m/z: [M + H]+ Calcd for C H BrN OH
19
15
2
1
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
7.15 (d, J = 7.55 Hz, 2H), 2.56 (s, 3H); C NMR (125 MHz,
CDCl ): δ =197.1, 168.9, 154.0, 148.6, 147.8, 142.9, 136.7,
134.6, 129.4, 129.3, 127.9, 127.1, 126.7, 124.7, 124.5, 26.6;
HRMS (ESI/TOFꢀQ) m/z: [M
367.0446; Found 367.0427.
3
N-phenyl-N-(pyridin-4-yl)picolinamide (3na): white solid (36
o
1
+
Na]+ Calcd for
mg, 66 %), Mp (117ꢀ119 C). H NMR (400 MHz, CDCl
= 10.18 (s, 1H), 8.59ꢀ8.58 (m, 4H), 8.25 (d, J = 7.76 Hz, 1H),
.04ꢀ8.03 (m, 1H), 7.89 (t, J = 7.52 Hz, 1H), 7.72 (s, 3H),
3
): δ
C H N O Na 339.1059; Found 339.1089.
20 16
2
2
8
13
N-(4-cyanophenyl)-N-phenylpicolinamide (3ha): pale yellow
solid (51 mg, 85%), Mp (108ꢀ110 C). H NMR (500 MHz,
CDCl ): δ = 8.33 (d, J = 4.45 Hz, 1H), 7.76ꢀ7.74 (m, 2H), 7.60
7.50ꢀ7.47 (m, 1H), 7.36 (s, 1H); C NMR (100 MHz, CDCl3):
δ = 162.8, 150.3, 148.7, 148.1, 144.8, 137.9, 133.6, 129.4,
127.5, 127.1, 122.7, 113.9; HRMS (ESI/TOFꢀQ) m/z: [M +
H]+ Calcd for C H N OH 276.1137; Found 276.1129.
o
1
3
(d, J = 8.60 Hz, 2H), 7.34ꢀ7.23 (m, 6H), 7.15 (d, J = 4.50 Hz,
17
13
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
2
1
1
H); C NMR (125 MHz, CDCl ): δ = 168.8, 153.4, 148.5,
3
47.5, 142.5, 136.8, 132.9, 129.5, 128.0, 127.4, 127.0, 124.9,
24.6, 118.5, 109.4; HRMS (ESI/TOFꢀQ) m/z: [M + Na]+
N-phenyl-N-(pyridin-4-yl)picolinamide (3oa): white solid
o 1
(42mg, 73 %), Mp (86ꢀ88 C). H NMR (400 MHz, CDCl ): δ
3
Calcd for C H N ONa 322.0956; Found 322.0960.
= 8.35 (s, 1H), 7.56 (t, J = 7.12 Hz, 1H), 7.43ꢀ7.41 (m, 1H),
2
0
16
2
7.33ꢀ7.23 (m, 5H), 7.11ꢀ7.07 (m, 4H), 6.93ꢀ6.92 (m, 2H), 5.15
13
N-phenyl-N-(4-(trifluoromethyl)phenyl)picolinamide
white solid (62 mg, 89%), Mp (95ꢀ97 C). H NMR (400
MHz, CDCl ): δ = 8.31 (dt, J = 4.92 Hz, J = 1.20 Hz, 1H),
7
4
1
=
1
(3ia):
(s, 2H); C NMR (125 MHz, CDCl ): δ = 168.8, 154.3, 148.6,
3
o
1
142.7, 137.1, 136.2, 134.3, 128.9, 128.5, 127.7, 127.5, 126.8,
123.9, 123.7, 53.6; HRMS (ESI/TOFꢀQ) m/z: [M + H]+ Calcd
1
2
3
.70ꢀ7.69 (m, 2H), 7.54 (d, J = 8.40 Hz, 2H), 7.31ꢀ7.26 (m,
for C H N OH 289.1341; Found 289.1349.
19 16 2
1
3
H), 7.22ꢀ7.13 (m, 4H); C NMR (100 MHz, CDCl ): δ =
3
68.8, 153.8, 148.5, 146.6, 142.9, 136.7, 129.3, 128.1 (q, JCꢀF
N-(4-fluorobenzyl)-N-phenylpicolinamide (3pa): white solid
o 1
32.00 Hz), 127.8, 127.1, 127.0, 126.17 (q, J = 3.64 Hz),
(55 mg, 89 %), Mp (106ꢀ108 C). H NMR (400 MHz,
CDCl ): δ = 8.33 (s, 1H), 7.56 (t, J = 7.08 Hz, 1H), 7.42ꢀ7.41
(m, 1H), 7.30ꢀ7.27 (m, 2H), 7.12ꢀ7.07 (m, 4H), 6.97ꢀ6.90 (m,
CꢀF
1
9
24.7, 124.5, 123.9 (q, JCꢀF = 270.28 Hz); F NMR (470 MHz,
3
CDCl ): δ −62.41 (s, 3F); HRMS (ESI/TOFꢀQ) m/z: [M + H]+
Calcd for C H F N OH 343.1058; Found 343.1034.
3
13
4H), 5.10 (s, 2H); C NMR (125 MHz, CDCl
): δ = 168.8,
1
9
13
3
2
3
1
62.3 (d, JCꢀF = 244.10 Hz), 154.2, 148.6, 142.6, 136.2, 132.9
N-(3-nitrophenyl)-N-phenylpicolinamide (3ja): white solid
(d, JCꢀF = 3.33 Hz), 130.5 (d, JCꢀF = 7.91 Hz), 129.0, 127.8,
o
1
(53 mg, 83%), Mp (118ꢀ120 C). H NMR (400 MHz, CDCl ):
126.9, 123.9 (d, J = 35.38 Hz), 115.4 (d, JCꢀF = 21.2 Hz),
3
CꢀF
1
2
19
δ = 8.32 (dt, J = 4.68 Hz, J = 1.32 Hz, 1H), 7.71ꢀ7.66 (m,
2H), 7.35ꢀ7.26 (m, 4H), 7.21ꢀ7.15 (m, 6H); C NMR (100
MHz, CDCl ): δ = 168.7, 154.0, 148.5, 144.7, 142.9, 136.6,
130.2, 129.6, 129.3, 127.6, 126.9, 126.0, 124.6, 124.4, 122.4;
HRMS (ESI/TOFꢀQ) m/z: [M + H]+ Calcd for C H N O H
3
52.9; F NMR (470 MHz, CDCl3): δ −114.99 (s, 1F); HRMS
1
3
(ESI/TOFꢀQ) m/z: [M + H]+ Calcd for C H FN OH
1
9
15
2
307.1247; Found 307.1245.
3
N-(4-methoxyphenethyl)-N-phenylpicolinamide (3qa): white
solid (45 mg, 67 %), Mp (109ꢀ111 C). H NMR (400 MHz,
18 13
3
3
o
1
20.1035; Found 320.1042.
CDCl ): δ = 8.33 (s, 1H), 7.56ꢀ7.53 (m, 1H), 7.37ꢀ7.35 (m,
3
N-(3-methoxyphenyl)-N-phenylpicolinamide (3ka): yellow
liquid (55 mg, 90%), Mp (80ꢀ82 C). H NMR (500 MHz,
CDCl ): δ = 8.36 (s, 1H), 7.67ꢀ7.63 (m, 2H), 7.27ꢀ7.17 (m,
7
CDCl ): δ = 168.8, 160.1, 154.5, 144.4, 143.3, 136.5, 129.7,
1
HRMS (ESI/TOFꢀQ) m/z: [M + H]+ Calcd for C H N O H
3
1H), 7.15ꢀ7.13 (m, 6H), 6.97 (s, 2H), 6.81 (d, J = 7.96 Hz,
o
1
2H), 4.12 (t, J = 6.76 Hz, 2H), 3.77 (s, 3H), 2.94 (t, J = 7.92
13
Hz, 2H); C NMR (100MHz, CDCl ): δ = 168.6, 158.3,
3
3
13
H), 6.74ꢀ6.72 (m, 3H), 3.70 (s, 3H); C NMR (125 MHz,
154.6, 148.6, 143.1, 136.2, 130.9, 129.9, 129.1, 127.7, 126.7,
123.9, 123.7, 114.0, 55.3, 52.1, 33.0; HRMS (ESI/TOFꢀQ)
m/z: [M + Na]+ Calcd for C H N O Na 355.1422; Found
3
29.1, 127.4, 126.6, 124.3, 124.2, 119.9, 113.3, 112.5, 55.4;
21
20
2
2
355.1426.
1
9
16
2
2
05.1290; Found 305.1288.
N-(3,4-dimethoxyphenethyl)-N-phenylpicolinamide
white solid (65 mg, 90 %), Mp (108ꢀ110 C). H NMR (400
(3ra):
o
1
N-(3,5-dimethylphenyl)-N-phenylpicolinamide (3la): white
solid (45 mg, 75%), Mp (127ꢀ129 C). H NMR (400 MHz,
CDCl ): δ = 8.35 (d, J = 4.52 Hz, 1H), 7.66ꢀ7.60 (m, 2H),
7
MHz, CDCl ): δ = 168.9, 154.7, 148.5, 143.5, 143.1, 138.8,
1
o
1
MHz, CDCl ): δ = 8.30 (s, 1H), 7.52 (s, 1H), 7.34 (s, 1H),
3
7.13ꢀ7.09 (m, 4H), 6.92 (s, 2H), 6.75 (s, 3H), 4.14ꢀ4.11 (m,
2H), 3.82ꢀ3.81 (m, 6H), 2.96ꢀ2.93 (m, 2H); C NMR
3
1
3
13
.26ꢀ7.13 (m, 6H), 6.82 (s, 3H), 2.21 (s, 6H); C NMR (100
(100MHz, CDCl ): δ = 168.6, 154.5, 148.9, 148.5, 147.6,
3
3
36.4, 129.0, 128.5, 127.3, 126.3, 124.2, 124.1, 21.2; HRMS
143.1, 136.1, 131.4, 129.0, 127.7, 126.7, 123.8, 123.6, 120.9,
112.2, 111.3, 56.0, 55.9, 52.0, 33.4; HRMS (ESI/TOFꢀQ) m/z:
[M + H]+ Calcd for C H N O H 363.1709; Found 363.1696.
(ESI/TOFꢀQ) m/z: [M + Na]+ Calcd for C H N ONa
2
0
18
2
3
25.1517; Found 325.1510.
22
22
2
3
N-(4-bromo-3-methylphenyl)-N-phenylpicolinamide
white solid (68 mg, 91 %), Mp (96ꢀ98 C). H NMR (400
MHz, CDCl ): δ = 8.33 (dt, J = 4.72 Hz, J = 1.20 Hz, 1H),
7.70ꢀ7.64 (m, 2H), 7.42 (d, J = 6.88 Hz, 1H), 7.29ꢀ7.10 (m,
7H), 6.87 (s, 1H), 2.30 (s, 3H); C NMR (100 MHz, CDCl3):
δ = 168.8, 154.1, 148.6, 143.1, 142.5, 138.9, 136.7, 132.8,
129.4, 129.2, 127.4, 126.8, 126.2, 124.5, 124.3, 122.7, 23.0;
(3ma):
N-butyl-N-phenylpicolinamide (3sa): yellow liquid (45 mg, 90
o
1
1
%). H NMR (400 MHz, CDCl ): δ = 8.29 (s, 1H), 7.50 (s,
3
1
2
1H), 7.32 (s, 1H), 7.15ꢀ7.02 (m, 6H), 3.93ꢀ3.90 (m, 2H), 1.59
3
(quint, J = 7.50 Hz, 2H), 1.37ꢀ1.32 (m, 2H), 0.87 (t, J = 6.40
1
3
13
Hz, 3H); C NMR (100MHz, CDCl ): δ = 168.5, 154.7,
3
148.5, 142.8, 136.1, 128.9, 127.7, 126.6, 123.7, 123.5, 49.8,
29.7, 20.1, 13.8; HRMS (ESI/TOFꢀQ) m/z: [M + Na]+ Calcd
for C H N ONa 277.1317; Found 277.1307.
16 18
2
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 9
1
3
N-cyclopropyl-N-phenylpicolinamide (3ta): yellow solid (26
2H); C NMR (125 MHz, MeOHꢀd ): δ = 170.7, 158.0, 155.9,
4
o
1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
mg, 55 %), Mp (53ꢀ55 C). H NMR (400 MHz, CDCl ): δ =
149.7, 144.5, 138.5, 135.7, 130.2, 128.0, 125.8, 125.1, 116.8;
HRMS (ESI/TOFꢀQ) m/z: [M + H]+ Calcd for C H N O H
291.1134; Found 291.1118.
3
1
2
8.42 (d, J = 3.88 Hz, 1H), 7.63 (td, J = 7.72 Hz, J = 1.32 Hz,
1H), 7.44 (d, J = 7.72 Hz, 1H), 7.27ꢀ7.23 (m, 2H), 7.19ꢀ7.12
(m, 4H), 3.37 (sept, J = 3.71 Hz, 1H), 0.80ꢀ0.78 (m, 2H), 0.57ꢀ
1
8
14
2
2
1
3
0
1
8
.53 (m, 2H); C NMR (100MHz, CDCl ): δ = 170.3, 155.3,
N-(3-bromophenyl)-N-phenylpicolinamide (4ai): white solid
(50 mg, 70%), Mp (115ꢀ117 C). H NMR (400 MHz, CDCl
δ = 8.33 (dt, J = 4.80 Hz, J = 1.32 Hz, 1H), 7.71ꢀ7.66 (m, 2H),
7.34ꢀ7.26 (m, 4H), 7.20ꢀ7.15 (m, 6H); C NMR (100 MHz,
3
o
1
48.5, 141.9, 136.4, 128.8, 127.8, 126.7, 123.9, 123.2, 32.4,
.5; HRMS (ESI/TOFꢀQ) m/z: [M + Na]+ Calcd for
3
):
1
2
13
C H N ONa 261.1004; Found 261.1012.
15
14
2
CDCl ): δ = 168.8, 153.9, 148.6, 144.6, 142.9, 136.7, 133.9,
3
N-allyl-N-phenylpicolinamide (3ua): white liquid (41 mg, 85
130.2, 129.6, 129.3, 127.6, 126.9, 126.0, 124.6, 124.4, 122.5;
HRMS (ESI/TOFꢀQ) m/z: [M + H]+ Calcd for C H N OBrH
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
%
). H NMR (400 MHz, CDCl ): δ = 8.33 (s, 1H), 7.57 (s,
3
18 13
2
1
5
H), 7.42 (s, 1H), 7.17ꢀ7.04 (m, 6H), 6.03ꢀ5.94 (m, 1H), 5.23ꢀ
.15 (m, 2H), 4.54 (d, J = 5.84 Hz, 2H); C NMR (100MHz,
353.0290; Found 353.0305.
13
CDCl ): δ = 168.6, 154.4, 148.6, 143.0, 136.2, 132.9, 128.9,
N-(3-formylphenyl)-N-phenylpicolinamide (4aj): pale yellow
3
o
1
1
27.5, 126.7, 124.0, 123.7, 118.3, 53.0; HRMS (ESI/TOFꢀQ)
solid (50 mg, 83%), Mp (114ꢀ116 C). H NMR (400 MHz,
CDCl ): δ = 9.91 (s, 1H), 8.31ꢀ8.29 (m, 1H), 7.72ꢀ7.67 (m,
4H), 7.51ꢀ7.45 (m, 2H), 7.30ꢀ7.26 (m, 2H), 7.21ꢀ7.15 (m, 4H);
m/z: [M + H]+ Calcd for C H N OH 239.1184; Found
3
1
5
14
2
239.1171.
1
3
C NMR (100 MHz, CDCl ): δ = 191.4, 168.8, 153.7, 148.4,
3
N-(2-(1H-indol-3-yl)ethyl)-N-phenylpicolinamide (3va): pale
144.3, 142.8, 137.2, 136.7, 132.9, 129.7, 129.3, 127.8, 127.6,
127.4, 127.0, 124.6, 124.4; HRMS (ESI/TOFꢀQ) m/z: [M +
Na]+ Calcd for C H N O Na 325.0953; Found 325.0940.
o
1
yellow solid (61 mg, 90 %), Mp (130ꢀ132 C). H NMR (500
MHz, CDCl ): δ = 8.36 (s, 1H), 8.22 (s, 1H), 7.58ꢀ7.52 (m,
3
19 14
2
2
2
7
H), 7.37 (d, J = 7.80 Hz, 1H), 7.33 (d, J = 8.05 Hz, 1H),
13
.17ꢀ7.02 (m, 9H), 4.27ꢀ4.25 (m, 2H), 3.17ꢀ3.15 (m, 2H);
C
N-phenyl-N-(thiophen-3-yl)picolinamide (4ak): pale yellow
o 1
NMR (125 MHz, CDCl ): δ = 168.7, 154.6, 148.6, 143.0,
solid (29 mg, 52%), Mp (99ꢀ101 C). H NMR (400 MHz,
3
1
1
1
36.3, 136.2, 129.1, 127.8, 127.5, 126.8, 123.9, 123.6, 122.2,
22.0, 119.4, 118.9, 112.8, 111.2, 50.9, 23.5; HRMS
CDCl
3
): δ = 8.34 (d, J = 4.32 Hz, 1H), 7.64 (td, J = 7.72 Hz,
2
J = 1.60 Hz, 1H), 7.58ꢀ7.56 (m, 1H), 7.27ꢀ7.14 (m, 7H), 6.98
(s, 2H); C NMR (100 MHz, CDCl ): δ = 168.3, 154.5, 148.6,
3
13
(
ESI/TOFꢀQ) m/z: [M + H]+ Calcd for C H N OH 342.1606;
2
2
19
3
Found 342.1593.
142.8, 141.5, 136.5, 129.1 (2×C), 127.6, 127.0, 125.2, 124.7,
124.2, 123.8; HRMS (ESI/TOFꢀQ) m/z: [M + H]+ Calcd for
C H N OSH 281.0749; Found 281.0767.
N-(4-bromophenyl)-N-phenylpicolinamide (4ad): white solid
16
12
2
o
1
(59 mg, 84%), Mp (127ꢀ129 C). H NMR (500 MHz, CDCl ):
3
δ = 8.33 (d, J = 4.50 Hz, 1H), 7.70ꢀ7.66 (m, 2H), 7.40 (d, J =
N-(4-bromophenyl)-N-(p-tolyl)picolinamide (4wb): white solꢀ
o 1
1
3
4
.90 Hz, 2H), 7.27ꢀ7.04 (m, 8H); C NMR (125 MHz,
id (67 mg, 91%), Mp (127ꢀ129 C). H NMR (500 MHz,
1 2
CDCl ): δ = 168.7, 154.0, 148.5, 143.0, 142.5, 136.6, 132.2,
CDCl
7.62 (m, 2H), 7.38 (s, 2H), 7.19ꢀ7.06 (m, 7H), 2.29 (s, 3H);
3
): δ = 8.34 (dt, J = 4.75 Hz, J = 1.25 Hz, 1H), 7.68ꢀ
3
1
29.2, 128.8, 127.5, 126.8, 124.5, 124.3, 120.0; HRMS
1
3
(
ESI/TOFꢀQ) m/z: [M + Na]+ Calcd for C H BrN ONa
C NMR (100 MHz, CDCl
140.4, 136.7, 136.6, 132.1, 129.9, 128.6, 127.3, 124.4, 124.2,
19.8, 21.1; HRMS (ESI/TOFꢀQ) m/z: [M + Na]+ Calcd for
C H N OBrNa 389.0265; Found 389.0244.
3
): δ = 168.7, 154.2, 148.6, 142.6,
1
8
13
2
3
75.0109; Found 375.0101.
1
N-(4-fluorophenyl)-N-phenylpicolinamide (4ae): white solid
19
15
2
o
1
(
56 mg, 90%), Mp (110ꢀ112 C). H NMR (500 MHz, CDCl ):
3
δ = 8.33ꢀ8.32 (m, 1H), 7.68ꢀ7.64 (m, 2H), 7.26ꢀ7.15 (m, 8H),
N-allyl-N-(4-bromophenyl)picolinamide (4ud): white liquid
13
1
6
.97 (s, 2H); C NMR (125 MHz, CDCl ): δ = 168.8, 160.9
(50 mg, 79%) H NMR (400 MHz, CDCl3): δ = 8.32 (s, 1H),
3
(d, JCꢀF = 245.27 Hz), 154.2, 148.5, 143.3, 139.4, 136.6,
7.62 (t, J = 6.80 Hz, 1H), 7.50ꢀ7.49 (m, 1H), 7.29ꢀ7.26 (m
129.1 (2×C), 127.3, 126.6, 124.3 (d, JCꢀF = 16.78 Hz), 115.9
2H), 7.15 (s, 1H), 6.91 (s, 2H), 5.99ꢀ5.89 (m, 1H), 5.20ꢀ5.14
1
9
13
(d, JCꢀF = 22.65 Hz); F NMR (470 MHz, CDCl ): δ −115.15
(m, 2H), 4.49 (d, J = 5.92 Hz, 2H); C NMR (100 MHz,
3
(s, 1F); HRMS (ESI/TOFꢀQ) m/z: [M + Na]+ Calcd for
C H FN ONa 315.0910; Found 315.0934.
CDCl ): δ = 168.3, 153.8, 148.5, 142.1, 136.5, 132.6, 132.0,
3
129.0, 124.3, 123.9, 120.3, 118.4, 53.0; HRMS (ESI/TOFꢀQ)
m/z: [M + H]+ Calcd for C H N OBrH 317.0290; Found
18
13
2
15
13
2
N-(4-formylphenyl)-N-phenylpicolinamide (4ag): pale yellow
317.0278.
o
1
solid (40 mg, 66%), Mp (107ꢀ109 C). H NMR (400 MHz,
1
2
CDCl ): δ = 9.94 (s, 1H), 8.30 (dt, J = 4.68 Hz, J = 1.28 Hz,
N,N-bis(4-methoxyphenyl)picolinamide (4dl): pale brown solꢀ
3
o
1
1
7
1
1
H), 7.81ꢀ7.78 (m, 2H), 7.74ꢀ7.68 (m, 2H), 7.33ꢀ7.27 (m 4H),
id (47 mg, 70%), Mp (107ꢀ109 C). H NMR (400 MHz,
13
1
2
.24ꢀ7.15 (m, 4H); C NMR (100 MHz, CDCl ): δ = 191.1,
CDCl
): δ = 8.37ꢀ8.35 (m, 1H), 7.63 (td, J = 7.66, Hz, J =
3
3
68.8, 153.6, 148.9, 148.5, 142.7, 136.7, 133.7, 130.4, 129.4,
27.9, 127.2, 126.9, 124.8, 124.5; HRMS (ESI/TOFꢀQ) m/z:
1.72 Hz, 1H), 7.57ꢀ7.55 (m, 1H), 7.25ꢀ6.80 (m, 9H), 3.75 (s,
13
6H); C NMR (125 MHz, CDCl ): δ = 168.9, 157.9, 154.8,
3
[
M + H]+ Calcd for C H N O H 303.1134; Found 303.1127.
148.6, 136.4, 129.0, 127.7, 124.0 (2×C), 114.3, 55.5; HRMS
(ESI/TOFꢀQ) m/z: [M + H]+ Calcd for C H N O H
1
9
14
2
2
20
18
2
3
N-(4-hydroxyphenyl)-N-phenylpicolinamide (4ah): white solid
335.1396; Found 335.1378.
o
1
(32 mg, 55%), Mp (203ꢀ205 C). H NMR (400 MHz, MeOHꢀ
1
2
d ): δ = 8.38ꢀ8.37 (m, 1H), 7.75 (td, J = 7.76 Hz, J = 1.64 Hz,
N-(2-(1H-indol-3-yl)ethyl)-N-(4-bromophenyl)picolinamide
4
o
1
1
H), 7.54 (d, J = 7.76 Hz, 1H), 7.32ꢀ7.05 (m, 8H), 6.68 (s,
(4vd): yellow solid (59 mg, 70%), Mp (134ꢀ136 C). H NMR
6
ACS Paragon Plus Environment

Page 7 of 9
The Journal of Organic Chemistry
13
(
400 MHz, CDCl ): δ = 8.40ꢀ8.34 (m, 2H), 7.56 (t, J = 7.20
(m, 2H), 6.28 (t, J = 2.08 Hz, 1H), 3.73 (s, 3H) ; C NMR(100
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Hz, 2H), 7.14ꢀ6.82 (m, 10H), 4.21ꢀ4.18 (m, 2H), 3.13ꢀ3.10 (m,
MHz, CDCl ): δ = 170.3, 161.2, 143.9, 140.9, 138.9, 137.9,
3
13
2H); C NMR (125 MHz, CDCl ): δ = 168.5, 154.0, 148.5,
131.4,
130.7, 130.2, 129.3, 128.9, 128.1, 127.3, 127.2,
3
136.5, 136.3, 132.1, 129.2, 127.4, 124.2, 123.7, 122.3, 122.0,
120.3, 119.3, 118.7, 112.4, 111.3, 51.0, 23.5; HRMS
126.9, 126.0, 113.1, 106.9, 55.3; HRMS (ESI/TOFꢀQ) m/z:
[M + H]+Calcd for C H N O H 370.1556; Found 370.1573.
23
19
3
2
(
ESI/TOFꢀQ) m/z: [M + H]+ Calcd for C H N OBrH
22 18 3
4
20.0711; Found 420.0721.
N-(2-(1H-pyrazol-1-yl)phenyl)-3-fluoro-N-phenylbenzamide
o 1
(5da): white solid (56 mg, 78%), Mp (155ꢀ157 C). H NMR
N-(2-(1H-indol-3-yl)ethyl)-N-(4-cyanophenyl)picolinamide
(400 MHz, CDCl ): δ = 7.68ꢀ7.60 (m, 2H), 7.45ꢀ7.38 (m, 3H),
3
o
1
(4vj): pale yellow solid (38 mg, 52%), Mp (162ꢀ164 C). H
7.26ꢀ7.24 (m, 1H), 7.19ꢀ7.08 (m, 8H), 6.96ꢀ6.91 (m, 1H), 6.32
1
13
NMR (400 MHz, CDCl ): δ = 8.30ꢀ8.25 (m, 2H), 7.65 (td, J =
(s, 1H); C NMR (125 MHz, CDCl ): δ = 169.0, 162.0 (d, J
3
3
CꢀF
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
7
8
7
.68 Hz, J = 1.40 Hz, 1H), 7.58ꢀ7.50 (m, 2H), 7.42 (d, J =
.24 Hz, 2H), 7.31 (d, J = 8.08 Hz, 1H), 7.21ꢀ7.14 (m, 2H),
.09ꢀ7.00 (m, 4H), 4.26 (t, J = 7.66 Hz, 2H), 3.15 (t, J = 7.64
= 245.4 Hz), 143.1, 141.1, 138.2, 137.7, 137.5 (d, JCꢀF = 7.12
Hz), 130.5, 130.1, 129.4 (2×C), 129.3, 129.0, 128.4, 127.0,
126.6, 124.8, 117.3 (d, J = 21.12 Hz), 116.2 (d, JCꢀF = 22.98
CꢀF
13
19
Hz, 2H); C NMR (125 MHz, CDCl3): δ = 168.4, 153.3,
48.3, 147.5, 136.8, 136.3, 132.8, 127.7, 127.3, 124.8, 124.3,
Hz), 107.0; F NMR (470 MHz, CDCl3): δ −112.64 (s, 1F);
1
HRMS (ESI/TOFꢀQ) m/z: [M + Na]+Calcd for C H FN ONa
22
16
3
122.3, 122.2, 119.5, 118.7, 118.4, 112.3, 111.3, 109.8, 51.4,
23.9; HRMS (ESI/TOFꢀQ) m/z: [M + H]+ Calcd for
C H N OH 367.1559; Found 367.1550.
380.1175; Found 380.1174.
N-(2-(1H-pyrazol-1-yl)phenyl)-N-phenylisonicotinamide
23
18
4
o
1
(
5ea): white solid (54 mg, 80%), Mp (157ꢀ159 C). H NMR
General procedure for the copper catalysed C–N cross-
coupling of aryl silanes: In a dried schlenk tube, the AgF (20
mol%) was taken inside the glovebox, the carboxamides 5
(500 MHz, CDCl ): δ = 8.45 (s, 2H), 7.73ꢀ7.69 (m, 2H), 7.46ꢀ
3
13
7.11 (m, 11H), 6.33 (s, 1H), C NMR (125 MHz, CDCl ): δ =
3
168.0, 149.7, 143.1, 141.2, 137.6, 130.7, 129.2, 128.7, 127.8,
127.1, 126.9, 122.8, 107.1; HRMS (ESI/TOFꢀQ) m/z: [M +
H]+Calcd for C H N OH 341.1402; Found 341.1420.
(
(
0.20 mmol), aryl silane derivative 6 (0.60 mmol), Cu(OAc)2
30 mol%), Ag2O (1 equiv.), were added under nitrogen atꢀ
21
16
4
mosphere. Then DMSO (1.5 mL) was added with a syringe,
subsequently purged the oxygen and allowed to stir at 80 oC
for 24 h. After completion of the reaction (TLC monitored), it
was extracted with saturated NaHCO3 solution and EtOAc.
The organic layer was dried with Na2SO4 and the solvent was
evaporated under reduced pressure. The resulting residue was
purified by column chromatography on silica gel with a
gradient eluent of hexane and ethyl acetate to give pure
products.
N-(2-(1H-pyrazol-1-yl)phenyl)-N-phenylfuran-3-carboxamide
o
1
(5fa): pale yellow solid (63 mg, 96%), Mp (122ꢀ124 C). H
NMR (400 MHz, CDCl ): δ = 7.64ꢀ7.63 (m, 2H), 7.54ꢀ7.51
(m, 1H), 7.45ꢀ7.36 (m, 3H), 7.25ꢀ7.14 (m, 5H), 7.07ꢀ7.05 (m,
3
13
2H), 6.33 (t, J = 2.00 Hz, 1H), 6.14 (s, 1H); C NMR (125
MHz, CDCl ): δ = 163.9, 146.7, 142.4, 142.2, 141.0, 138.2,
137.5, 130.5, 130.4, 129.2, 128.8, 127.2, 121.8, 110.8, 107.1;
HRMS (ESI/TOFꢀQ) m/z: [M Na]+ Calcd for
C H N O Na 352.1062; Found 352.1078.
3
+
20 15
3
2
N-(2-(1H-pyrazol-1-yl)phenyl)-4-methyl-N-phenylbenzamide
o
1
(
5aa): white solid (65 mg, 96%), Mp (147ꢀ149 C). H NMR
N-(2-(1H-pyrazol-1-yl)phenyl)-N-phenylfuran-3-carboxamide
o 1
(
400 MHz, CDCl ): δ = 7.65 (d, J = 1.6 Hz, 2H), 7.49ꢀ7.47 (m,
(7aa): pale brown solid (64 mg, 91%), Mp (182ꢀ184 C). H
NMR (400 MHz, CDCl ): δ = 7.91 (s, 1H), 7.50 (d, J = 7.28
Hz, 2H), 7.39ꢀ7.10 (m, 11H), 4.26 (t, J = 8.76 Hz, 2H), 3.91
3
1
7
1
1
1
H), 7.39ꢀ7.36 (m, 2H), 7.28ꢀ7.23 (m, 3H), 7.16ꢀ7.12 (m, 2H),
3
.08ꢀ7.02 (m, 3H), 6.94 (d, J = 7.92, 2H), 6.29 (t, J = 2.1,
13
13
H), 2.25 (s, 3H) ; C NMR(100 MHz, CDCl ): δ = 170.6,
(t, J = 8.40 Hz, 2H); C NMR (125 MHz, CDCl ): δ = 170.4,
3
3
43.7, 140.9, 140.7, 138.7, 137.9, 132.3, 130.7, 130.2, 129.3,
28.9, 128.4, 128.2, 127.1, 127.0, 126.1, 106.8, 21.5; HRMS
163.2, 144.2, 142.6, 136.1, 131.8, 130.9, 130.1, 129.2, 128.8,
127.8, 127.0, 126.4, 126.0, 67.5, 54.9; HRMS (ESI/TOFꢀQ)
(
ESI/TOFꢀQ) m/z: [M + Na]+Calcd for C H N ONa
m/z: [M + H]+Calcd for C22
343.1430.
H N O H 343.1447; Found
18 2 2
2
3
19
3
3
76.1426; Found 376.1409.
N-(2-(1H-pyrazol-1-yl)phenyl)-N-phenylbenzamide
white solid (65 mg, 96%), Mp (174ꢀ176 C). H NMR (400
(5ba):
Gram scale synthesis of compound 3va: The picolinamide (1v)
(4.1 mmol, 1.10 g, 1 equiv), phenyl boronic acid 2a (10.2
o
1
MHz, CDCl ): δ = 7.69 (d, J = 1.36 Hz, 2H), 7.50 (d, J = 4.64
mmol, 1.2 g, 2.5 equiv), Cu(OAc) ·H O (0.8 mmol, 163 mg,
2 2
3
Hz, 1H), 7.42ꢀ7.36 (m, 4H), 7.31ꢀ7.25 (m, 2H), 7.19ꢀ7.15 (m,
20 mol %), DMAP (0.8 mmol, 100 mg, 20 mol %), and KI
(0.8 mmol, 136 mg, 20 mol %) were taken in a dried Schlenk
flask with a magnetic stir. Then DME (50 mL) was added with
a syringe and the resulting mixture was allowed to stir for 48
h. After completion of the reaction (TLC monitored), it was
13
4
H), 7.11ꢀ7.07 (m, 3H), 6.33 (t, J = 2.02 Hz, 1H) ;
C
NMR(100 MHz, CDCl ): δ = 170.6, 143.5, 141.0, 138.5,
3
1
1
37.9, 135.3, 130.7, 130.3, 129.3, 129.2, 128.9, 128.3, 127.8,
27.1, 126.2, 106.9; HRMS (ESI/TOFꢀQ) m/z: [M +
Na]+Calcd for C H N ONa 362.1269; Found 362.1253.
transferred to a round bottom flask after dilution with CH Cl
2 2
22
17
3
and extracted with saturated NaHCO solution. The organic
3
N-(2-(1H-pyrazol-1-yl)phenyl)-4-methoxy-N-phenylbenzamide
layer was dried with Na SO . The solvent was evaporated to
2
4
o
1
(
5ca): white solid (65 mg, 96%), Mp (128ꢀ130 C). H NMR
dryness and the crude reaction mixture was loaded directly on
to silica gel column and purified to provide pure amide 3va
(1.15 g, 82%).
(400 MHz, CDCl ): δ = 7.63 (d, J = 1.56 Hz, 2H), 7.49ꢀ7.47
3
(m, 1H), 7.39ꢀ7.37 (m, 2H), 7.32 (d, J = 8.76 Hz, 2H ), 7.27ꢀ
7.24 (m, 1H), 7.17ꢀ7.13 (m, 2H), 7.08ꢀ7.01 (m, 3H), 6.67ꢀ6.63
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 9
Sequential N-arylation of the tryptamine derivative: In a dried characterization data for the prepared compounds (PDF), and
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Schlenk tube, the CsF (2 equiv.) was taken inside the gloveꢀ
box, the compound 3va (0.15 mmol), aryl iodide derivatives (2
equiv), CuI (20 mol %) were added under nitrogen atmosꢀ
phere. Then, DMSO (1.5 mL) was added with a syringe and
crystallographic data (CIF).
AUTHORS INFORMATION:
mbaidya@iitm.ac.in; pre@iitm.ac.in
o
allowed to stir at 130 C for 24 h. After completion of the reꢀ
action (TLC monitored), it was extracted with saturated Naꢀ
ACKNOWLEDGMENTS:
HCO solution and EtOAc. The organic layer was dried with
3
We gratefully acknowledge CSIR New Delhi for the financial
support (02(0212)/14/EMRꢀII). H.K.S thanks IITM for HTRA
and G.S.G. thanks UGC New Delhi for a JRF. We also thank the
Department of Chemistry, IITꢀMadras for instrumental facilities.
We also thank the Department of Chemistry, IITꢀMadras for
instrumental facilities.
Na SO and the solvent was evaporated under reduced presꢀ
2
4
sure. The resulting residue was purified by column chromaꢀ
tography on silica gel with a gradient eluent of hexane
and ethyl acetate to give the corresponding tryptamine derivꢀ
atives.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N-(2-(1-(4-methoxyphenyl)-1H-indol-3-yl)ethyl)-N-
phenylpicolinamide (8): yellow liquid (81 mg, 91%). H NMR
1
REFERENCES:
1
(1) (a) Greenberg, A.; Breneman, C. M.; Liebman, J. F. Amide
Linkage: Selected Structural Aspects in Chemistry, Biochemistry,
and Materials Science, WileyꢀInterscience, New York, 2000. (b)
Buckheit Jr, R. W.; Kinjerski, T. L., FliakasꢀBoltz, V.; Russell, J.
D.; Stup, T. L.; Pallansch, L. A.; Brouwer, W. G.; Dao, D. C.;
Harrison, W. A.; Schultz, R. J.; Bader, J. P.; Yang, S. S. Antimi-
(400 MHz, CDCl ): δ = 8.33 (s, 1H), 7.65 (s, 1H), 7.53 (td, J
3
2
= 7.72 Hz, J = 1.40 Hz, 1H), 7.42ꢀ7.33 (m, 5H), 7.19ꢀ6.98 (m,
10H), 4.29 (t, J = 6.76 Hz, 2H), 3.84 (s, 3H), 3.22 (t, J = 7.04
13
Hz, 2H); C NMR (125 MHz, CDCl ): δ = 168.7, 158.0,
3
1
1
1
54.5, 148.5, 143.0, 136.5, 136.2, 132.8, 129.0, 128.6, 127.7,
26.7, 126.2, 125.7, 123.8, 123.6, 122.3, 119.7, 119.2, 114.7,
13.3, 110.3, 55.6, 51.0, 23.4; HRMS (ESI/TOFꢀQ) m/z: [M +
crobial Agents and Chemotherapy
blum, S. B.; Huynh, T.; Afonso, A.; David Jr, H. R.; Yumibe, N.;
Clader, J. W.; Burnett, D. A. J. Med. Chem 1998 41, 973. (d)
Okubo, T.; Yoshikawa, R.; Chaki, S.; Okuyama, S.; Nakazato, A.
Bioorg. Med. Chem 2004 12, 423. (e) Roughley, S. D.; Jordan, A.
M. J. Med. Chem. 2011 54, 3451. (f) Pattabiraman, V. R.; Bode,
J. W. Nature 2011 480, 471. (g) Cogo, J.; Kaplum, V.; Sangi, D.
P.; UedaꢀNakamura, T.; Correa, A. G.; Nakamura, C. V.; Eur. J.
Med. Chem. 2015 90, 107. (h) Sun, YꢀH., Sun, TꢀY., Wu, YꢀD.,
. 1995, 39, 2718. (c) Rosenꢀ
.
,
H]+Calcd for C H N O H 448.2025; Found 448.2032.
29
25
3
2
.
,
N-phenyl-N-(2-(1-(thiophen-2-yl)-1H-indol-3-yl)
,
ethyl)picolinamide (9): yellow solid (50 mg, 59%), Mp (146ꢀ
.
,
o
1
1
48 C). H NMR (400 MHz, CDCl ): δ = 8.34 (s, 1H), 7.65
3
(s, 1H), 7.57ꢀ7.54 (m, 2H), 7.40 (d, J = 8.12 Hz, 1H), 7.25ꢀ
,
7
.01 (m, 12H), 4.28 (t, J = 7.52 Hz, 2H), 3.20 (t, J = 6.96 Hz,
Zhang, X.; Rao, Y. Chem. Sci
cited in.
.
2016
,
7
, 2229 and the references
13
2H); C NMR (125 MHz, CDCl ): δ = 168.7, 154.5, 148.6,
1
123.9, 123.7, 123.0, 121.2, 120.6, 119.8, 119.3, 114.7, 110.7,
50.8, 23.3; HRMS (ESI/TOFꢀQ) m/z: [M + Na]+Calcd for
C H N OSNa 446.1303; Found 446.1322.
3
(2) (a) Overman, L. E.; Watson, D. A. J. Org. Chem
587. (b) Shang, S.; ZhangꢀNegrerie, D.; Du, Y.; Zhao, K. Angew.
Chem. Int. Ed 2014 53, 6216. (c) Cyr, P.; Régnier, S.; Bechara,
W. S.; Charette, A. B. Org. Lett 2015 17, 3386. (d) Régnier, S.;
Bechara, W. S.; Charette, A. B. J. Org. Chem 2016 81, 10348.
(3) (a) Arnold, K.; Davies, B.; Herault, D.; Whiting, A. Angew.
Chem., Int. Ed 2008 47, 2673. (b) Charville, H.; Jackson, D.;
Hodges, G.; Whiting, A. Chem. Commun 2010 46, 1813. (c)
Allen, C. L.; Chhatwal, R. A.; Williams, J. M. J. Chem. Commun
.
2006 71,
,
41.8, 137.3, 136.2, 129.1, 128.8, 127.7, 127.1, 126.8, 126.1,
2
.
,
.
,
26 21
3
.
,
Synthesis of compound 10: The compound 3va (0.29 mmol,
00 mg, 1 equiv), and NaOH (400 mg) were taken in a dried
.
,
1
.
,
schlenk tube with a magnetic stir bar. Then EtOH (4 mL) was
added with a syringe and the resulting mixture was allowed to
stir at 80 C for 8 h. After completion of the reaction (TLC
monitored), it was diluted with DCM. The filtrate was evapoꢀ
rated to dryness and the crude reaction mixture was purified
by silica gel column chromatography to provide product 10.
.
2012
4) (a) Yoo, W. J.; Li, C. J. J. Am. Chem. Soc
13064. (b) Bode, J. W.; Sohn, S. S. J. Am. Chem. Soc
,
48, 666. (d) Ishihara, K.; Lu, Y. Chem. Sci
.
2016
,
7
, 1276.
o
(
.
2006
2007
,
,
128
129
,
,
.
13798. (c) Ghosh, S. C.; Ngiam, J. S. Y.; Seayad, A. M.; Tuan, D.
H.; Chai, C. L. L.; Chen, A. J. Org. Chem 2012 77, 8007.
5) (a) Gunanathan, C.; BenꢀDavid, Y.; Milstein, D. Science
.
,
(
.
2
007
,
317, 790. (b) Nordstrøm, L. U.; Vogt; H.; Madsen, R. J. Am.
2008 130, 17672. (c) Zweifel, T.; Naubron, J.ꢀV.;
Grutzmacher, H. Angew. Chem., Int. Ed 2009 48, 559. (d) Watꢀ
son, A. J. A.; Maxwell, A. C.; Williams, J. M. J. Org. Lett 2009
11, 2667. (e) Soule, J. F.; Miyamura, H.; Kobayashi, S. J. Am.
Chem. Soc 2011 133, 18550. (f) Yamaguchi, K.; Kobayashi, H.;
Oishi, T.; Mizuno, N. Angew. Chem., Int. Ed 2012 51, 544.
6) (a) Yamaguchi, K.; Matsushita, M.; Mizuno, N. Angew.
N-(2-(1H-indol-3-yl)ethyl)aniline (10): yellow solid (45 mg,
Chem. Soc
.
,
o
1
95%), Mp (114ꢀ116 C). H NMR (400 MHz, CDCl ): δ =
3
.
,
7.92 (brs, 1H), 7.60 (d, J = 7.88 Hz, 1H), 7.33ꢀ7.31 (m, 1H),
.
,
7
1
6
1
1
.21ꢀ7.09 (m, 4H), 6.98 (d, J = 2.12 Hz, 1H), 6.71ꢀ6.67 (m,
H), 6.61ꢀ6.59 (m, 2H), 3.45 (t, J = 6.82 Hz, 2H), 3.06 (t, J =
.
,
1
3
.
,
.76 Hz, 2H); C NMR (125 MHz, CDCl ): δ = 148.3, 136.5,
3
(
29.3, 127.5, 122.3, 122.1, 119.5, 118.9, 117.4, 113.5, 113.1,
11.3, 44.1, 25.2; HRMS (ESI/TOFꢀQ) m/z: [M + H]+Calcd
Chem., Int. Ed. 2004
,
43, 1576. (b) Ramon, R. S.; Marion, N.;
2009 15, 8695. (c) Mitsuꢀdome, T.;
Mikami, Y.; Mori, H.; Arita, S.; Mizugaki, T.; Jitsukawa, K.;
Kaneda, K. Chem. Commun 2009, 3258.
7) (a) Cho, S.; Yoo, E.; Bae, I.; Chang, S. J. Am. Chem. Soc
Nolan, S. P. Chem. Eur. J
.
,
for C H N H 237.1392; Found 237.1383.
16
16
2
.
ASSOCIATED CONTENTS:
Supporting Information:
(
.
2
005
,
127, 16046. (b) Chen, Z.ꢀW.; Jiang, H.ꢀF.; Pan, X.ꢀY.; He,
67, 5920.
(8) (a) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem
219, 131. (b) Surry, D. S. Buchwald, S. L. Chem. Sci 2011
Z.ꢀJ. Tetrahedron 2011
,
.
,
2002
2, 27.
,
The supporting information is available free of charge on the
ACS Publications website. Complete experimental details,
.
(c) Hartwig, J. F. Angew. Chem., Int. Ed
Hartwig, J. F. Acc. Chem. Res 2008 41, 1534.
.
1998
,
37, 2047. (d)
.
,
8
ACS Paragon Plus Environment

Page 9 of 9
The Journal of Organic Chemistry
(
9) (a) Handbook of “Synthetic Methods in Drug Discovery”,
Lam, P. Y. S. RSC 2016 , 242. (b) Lam, P. Y. S.; Clark, C. G.;
Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs,
A. Tetrahedron Lett 1998 39, 2941. (c) Chan, D. M. T.; Monaco,
K. L.; Wang, R.ꢀP.; Winters, M. P. Tetrahedron Lett
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
,
, 1
.
,
.
1998
,
39,
2
933. (d) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed 2003
.
,
42, 5400. (e) Qiao, J. X.; Lam, P. Y. S. Synthesis. 2011, 829. (f)
Vantourout, J. C.; Law, R. P.; IsidroꢀLlobet, A.; Atkinson, S. J.;
Watson, A. J. B. J. Org. Chem 2016 81, 3942. (g) Roy, S.; Sarꢀ
ma, M. J.; Kashyap, B.; Phukan, P. Chem. Commun. 2016 52
.
,
,
,
1
170.
0) (a) Gnanaprakasam, B.; Milstein, D. J. Am. Chem. Soc
011
1
.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
,
133, 1682. (b) Zhang, M.; Imm, S.; Bähn, S.; Neubert, L.;
Neumann, H.; Beller, M. Angew. Chem., Int. Ed. 2012
,
51, 3905.
(
1
c) Rao, S. N.; Mohan, D. C.; Adimurthy, S. Org. Lett
.
2013
496. (d) Do, H.ꢀQ.; Bachman, S.; Bissember, A. C.; Peters, J. C.;
2014 136, 2162.
11) Efficient protocol on Nꢀarylation of amides with aryl
, 15,
Fu, G. C. J. Am. Chem. Soc
.
,
(
ioꢀ
dides at elevated temperature using copperꢀchelating ligand catalytic
system, see: (a) Racine, E.; Monnier, F.; Vors, J.ꢀP.; Taillefer, M.
Org. Lett. 2011, 13, 2818. (b) Cristau, H.ꢀJ.; Cellier, P. P.; Spindler,
J.ꢀF.; Taillefer, M. Chem. Eur. J. 2004, 10, 5607.
(
12) For recent reviews, see: (a) Rouquet, G.; Chatani, N. An-
gew. Chem. Int. Ed 2013 52, 11726. (b) Liu, J.; Chen, G.; Tan, Z.
Adv. Synth. Catal 2016 358, 1174 and references cited therein.
13) For selective example for C–N bond formation under copꢀ
per catalysis: (a) Roane, J.; Daugulis, O. J. Am. Chem. Soc 2016
38, 4601. (b) Shang, M.; Sun, SꢀZ.; Dai, HꢀX.; Yu, JꢀQ. J. Am.
Chem. Soc 2014 136, 3354. (c) Jiao, J.; Murakami, K.; Itami, K.
ACS Catal 2016 , 610 and references cited therein.
14) (a) Urones, B.; Martınez, A. M.; Rodrıguez, N.; Arraya, R.
G.; Carretero, J. C. Chem. Commun 2013 49, 11044. (b) Li, Q.;
Zhang, SꢀY.; He, G.; Ai, Z.; Nack, W. A.; Chen, G. Org. Lett
014 16, 1764. (c) Martınez, A. M.; Rodrıguez, N.; Arraya, R. G.;
Carretero, J. C. Chem. Commun 2014 50, 2801. (d) Zhao, S.; Liu,
B.; Zhan, BꢀB.; Zhang, WꢀD.; Shi, BꢀF. Org. Lett 2016 18, 4586.
e) Gui, Q.; Chen, X.; Hu, L.; Wang, D.; Liu, J.; Tan, Z. Adv.
Synth. Catal 2016 358, 509. (f) Selvakumar, J.; Grandhi, G. S.;
Sahoo, H.; Baidya, M. RSC Adv 2016 , 79361.
15) Kathiravan, S.; Ghosh, S.; Hogarth, G.; Nicholls, I. A.
Chem. Commun 2015 51, 4834.
16) Improvement of reaction yields in the presence of halide
additives: (a) Hu, X. Chem. Sci. 2011 , 1867. (b) Lin, C.; Li, D.;
Wang, B.; Yao, J.; Zhand, Y. Org. Lett. 2015 17, 1328. (c)
Ackerman, L. K. G.; Lovell, M. M.; Weix, D. J. Nature. 2015
.
,
.
,
(
.
,
1
.
,
.
, 6
(
.
,
.
2
,
.
,
.
,
(
.
,
.
, 6
(
.
,
(
,
2
,
,
5
24, 454.
17) CCDC numbers of the crystal structures, 3aa: 1502266;
va: 1502267; 5aa: 1502268
18) (a) Collman, J. P.; Zhong, M. Org. Lett
Lam, P. Y. S.; Bonne, D.; Vicent, G.; Clark, C. G.; Combs, A. P.
Tetrahedron Lett 2003 44, 1691. (c) King, A. E.; Brunold, T. C.;
Stahl, S. S. J. Am. Chem. Soc 2009 131, 5044. (d) Rao, D. N.;
Rasheed, S.; Kumar, K. A.; Reddy, A. S. Dasa, P. Adv. Synth.
Catal 2016 358, 2126.
19) (a) Odani, R.; Hirano, K.; Satoh, T.; Miura, M. J. Org.
Chem 2013 78, 11045. (b) Martínez, Á.; Rodríguez, N.; Arrayás,
R.; Carretero, J. C. Chem. Commun., 2014 50, 2801. (c) Li, Q.;
Zhang, SꢀY.; He, G.; Ai, Z.; Nack, W. A.; Chen, G. Org. Lett
014 16, 1764.
20) See reference 14(f).
(
3
.
(
. 2000, 2, 1233. (b)
.
,
.
,
.
,
(
.
,
,
.
2
,
(
9
ACS Paragon Plus Environment