Direct para-Selective C-H Amination of Iodobenzenes: Highly Efficient Approach for the Synthesis of Diarylamines

Article abstract of DOI:10.1021/acs.joc.1c00681

Iodine(III)-mediated synthesis of 4-iodo-N-phenylaniline from iodobenzene has been achieved, and the reaction can proceed under mild conditions. A variety of functional groups were well tolerated, providing the corresponding products in moderate to good yields. The remaining iodine group provides an effective platform for converting the products into several valuable asymmetric diphenylamines. Most importantly, this reaction can be easily scaled up to the ten-gram scale, highlighting its synthetic utility. The mechanistic study revealed that the in situ generated aryl hypervalent iodine intermediate is the key factor to realize this para-selective C-H amination reaction.

Full text of DOI:10.1021/acs.joc.1c00681

pubs.acs.org/joc
Article
Direct para-Selective C−H Amination of Iodobenzenes: Highly
Efficient Approach for the Synthesis of Diarylamines
Yujie Chen, Zhibin Huang,* Yaqiqi Jiang, Sai Shu, Shan Yang, Da-Qing Shi,* and Yingsheng Zhao*
Cite This: J. Org. Chem. 2021, 86, 8226−8235
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Iodine(III)-mediated synthesis of 4-iodo-N-phenyl-
aniline from iodobenzene has been achieved, and the reaction can
proceed under mild conditions. A variety of functional groups were
well tolerated, providing the corresponding products in moderate
to good yields. The remaining iodine group provides an effective platform for converting the products into several valuable
asymmetric diphenylamines. Most importantly, this reaction can be easily scaled up to the ten-gram scale, highlighting its synthetic
utility. The mechanistic study revealed that the in situ generated aryl hypervalent iodine intermediate is the key factor to realize this
para-selective C−H amination reaction.
For example, the Csaky
̈
group8 recently reported the direct
́
1. INTRODUCTION
synthesis of diphenylamines from nitrosoarenes and boronic
acids (Scheme 1b). N-Arylation of amides with readily
available diaryliodonium salts also has been proposed by the
Olofsson group,9 and the metal-free direct amination of 2-
cyclohexenones to N-arylanilines promoted by iodine was
disclosed by Maycock10 in 2012.
Diarylamines are important chemicals that are often found in
natural products, agrochemicals, pharmaceuticals, organic
functional materials, and dyestuffs.1 The most widely used
diphenylamine synthetic methods are based on the metal-
catalyzed coupling of anilines and boronic acids or aryl halides
under Cu-catalysis (e.g., the Ullmann−Goldberg reaction2 and
Chan−Evans−Lam reaction3) or Pd-catalysis (e.g., the
Buchwald−Hartwig reaction4) (Scheme 1a). These methods
Recently, the para-benzylation of iodobenzene diacetate
with BnSiMe3 was disclosed by Hyatt11 and Shafir,12
respectively. Subsequently, Hyatt13 demonstrated that iodo-
benzenes can undergo para-selective benzylation via the in situ
formation of hypervalent iodine intermediates using Selectfluor
as the oxidant. In addition, Lei14 has reported a two-electron-
transfer oxidation-induced strategy for para-selective C−H
etherification of iodosobenzenes. The iodine group can be
easily transformed into other functional groups by various
coupling reactions; thus, it would be useful to construct
diarylamine skeletons with an iodine group. However, N-
nucleophiles are easily oxidized and quench the entire reaction
path, which is a general challenge. Herein, we report a general
protocol for the synthesis of diarylamines by treating aryl
iodides and anilides with mCPBA as the oxidant in
hexafluoroisopropanol (HFIP) under mild conditions. Achiev-
ing hypervalent iodide intermediates while keeping N-reactivity
is the key to achieve this transformation.
Scheme 1. Syntheses of Diarylamines and our Work
have been constantly improved by the development of new
ligands, precatalysts, and extensive investigations of the
reaction mechanisms.5 In addition, with the development of
C−H activation, the use of metal-catalyzed C−N bond
formation to prepare diphenylamines has been extensively
explored;6 however, most of these methods require the use of
toxic and expensive metal catalysts, which makes it necessary
to remove metal residues in many applications, such as in the
pharmaceutical industry. Hence, increasing attention has been
devoted to the development of metal-free synthetic strategies.7
Received: March 22, 2021
Published: June 3, 2021
https://doi.org/10.1021/acs.joc.1c00681
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 8226−8235
8226

The Journal of Organic Chemistry
2. RESULTS AND DISCUSSION
pubs.acs.org/joc
Article
a
Table 2. Substrate Scope of Iodobenzenes
mCPBA is a readily available and cheap oxidant that can
oxidize aryl iodides to hypervalent iodides, as disclosed by the
Chun group.15 Based on these results, we speculated that a
diarylamine could be directly prepared from iodobenzenes by
using mCPBA as the oxidant and anilides as the aminating
reagent. With these conditions in mind, Py, Pym, Tf, Cbz, PA,
and Ts-protected anilines were directly treated with
iodobenzene in the presence of mCPBA as the oxidant in
the HFIP solvent at 0 °C for 12 h (Table 1). p-
a
Table 1. Screening of Protecting Groups
a
Reaction conditions: 1k (0.2 mmol), 2 (0.4 mmol), mCPBA (0.4
mmol) in HFIP (1.0 mL) at 0 °C for 6 h in a sealed tube, isolated
yield after chromatography. Then, 4, NaOH (1.0 mmol) in EtOH
(1.0 mL) at 100 °C in an oil bath for 1 h in a sealed tube, isolated
yield after chromatography.
of the corresponding polysubstituted diarylamines (4d; 4f).
Next, disubstituted iodobenzenes were used for synthesis and
were found to be compatible with this reaction (4i−4l).
To further demonstrate the applicability of our new method
and avoid the effect of a tertiary amine on the 13C NMR
spectrum (see the Supporting Information), the deprotection
of the acetyl group was examined. After treatment with NaOH
or K2CO3 in ethanol under reflux conditions, the products
were isolated in different yields.
a
Reactions were carried out on a 0.2 mmol scale, 1 (0.2 mmol), 2a
(0.4 mmol), mCPBA (0.4 mmol) in HFIP (1.0 mL) at 0 °C for 12 h
in a sealed tube. Isolated yields were given.
Toluenesulfonanilide provided the product 3f in 8% yield.
We next turned our attention to the acyl protecting group. The
benzoyl-protected aniline afforded the aminated product 3h in
23% yield, while the trifluoroacetyl-protected aniline afforded
the aminated product 3i in 33% yield. When acetanilide was
used, the desired product was obtained in 86% yield. Pivaloyl-
protected aniline did not give the corresponding product 3g,
and the starting material was recovered, possibly because the
steric hindrance of the pivaloyl group reduced the reactivity of
substrate 1g. Subsequently, a variety of solvents such as DCE,
EtOH, t-Amyl-OH, AcOH, and TFE were investigated, and
HFIP was determined to be the best solvent. Other peroxide
oxidants, including H2O2, K2SO8, DTBP, TBHP, and Oxone,
were screened, but none provided satisfactory results in this
amination reaction (see the Supporting Information). A
control reaction revealed that the oxidant is indispensable for
this reaction. It is worth noting that the deiodination N-
arylation reaction was not observed under these reaction
conditions.9
After optimizing the reaction conditions, we investigated the
substrate scope of various iodobenzenes to explore the
versatility of this para-selective amination protocol. The results
are summarized in Table 2. Both the electron-donating group
(−Me, −Et, −iPr, and −CH2OC2H5) and the electron-
withdrawing group (−CF3) in iodobenzene were tolerated in
this reaction (4a−4c, 4e, and 4g). Additionally, ortho- and
meta-methyl-substituted iodobenzene (4a; 4h) produced
similar results, so the position of the methyl group in
iodobenzene did not affect the reaction yield. It should be
noted that iodobenzenes with halogen substituents, such as
bromine and fluorine, were suitable substrates for the synthesis
Next, we evaluated the reaction scope using various anilides,
and the results are summarized in Table 3. We found that this
reaction was tolerant to a variety of functional groups, such as
fluoride, chloride, bromide, phenyl, ester, acetoxy, and
trifluoromethyl groups. A small increase in temperature
(from 0 to 60 °C) was sometimes necessary to obtain better
transformation. The substrates containing nonsubstituted or
electron-withdrawing groups at the ortho, meta, and para-
position all provided the corresponding products in moderate
to good yields ranging from 52% to 89% (3j−3l; 3n−3v).
Meta-aromatic substitution afforded a biphenyl derivative
(3m). Interestingly, ortho and meta-iodoacetanilide also
afforded the corresponding products (3w; 3x) in 62% and
51% yields rather than the dimerization products. This might
provide a convenient means to install other functional groups
through known protocols. Indeed, the electron-donating group
(isopropyl) at the meta position was tolerated in this reaction,
and the desired product (3y) was obtained in 72% yield.
However, when we attempted the reaction with 3-methox-
yacetanilide, the desired product was not detected. These
observations indicated that the electronegativity of the
acetanilide substituent may greatly impact the reaction. This
reaction was not only suitable for monosubstituted substrates
but also for substrates bearing several substituents at different
positions. Substitutions with aliphatic and halide substituents
(3z, 3aa) were both well tolerated. Moreover, both meta and
para positions with a halide (3ab) gave very good results.
8227
https://doi.org/10.1021/acs.joc.1c00681
J. Org. Chem. 2021, 86, 8226−8235

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
a
a
Table 3. Substrate Scope of Anilides
Scheme 2. Gram-Scale Reaction and Transformation
a
Reaction conditions: (1) NaBH4 (15.0 eq), CuCl (75 mol %),
MeOH, 0 °C, 1 h. (2) Ethyl acrylate (2.0 equiv), Pd(OAc)2 (10 mol
%), PPh3 (5 mol %), Et3N, 100 °C, 24 h. (3) Phenylacetylrene (2.0
equiv), Pd(PPh3)4 (5 mol %), CuI (10 mol %), Et3N, 100 °C, 24 h.
(4) PhB(OH)2 (2.0 equiv), Pd(OAc)2 (10 mol %), K3PO4 (2.0
equiv), xantphos (20 mol %), Tol, N2, 120 °C, 16 h. (5) CuI (10 mol
%), KOH (5.0 equiv), Phen (20 mol %), DMSO/H2O = 1:1, 120 °C,
24 h.
Scheme 3. Mechanism Experiment
a
Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), mCPBA (0.4
mmol) in HFIP (1.0 mL) at 0 °C for 6 h in a sealed tube, isolated
yield after chromatography. Then, 3, NaOH (1.0 mmol) in EtOH
(1.0 mL) at 100 °C in an oil bath for 1 h in a sealed tube, isolated
b
c
yield after chromatography. 60 °C in an oil bath. K2CO3 instead of
d
NaOH. MeOH instead of EtOH.
To further demonstrate the practicality of this new reaction,
a more meaningful gram-scale reaction between 10 g of 1u and
2 equivalents of 2a was carried out at 0 °C. The desired
product 3u was isolated in 71% (13.8 g) (Scheme 2a),
highlighting the synthetic utility of this method. Furthermore,
the applicability of this method was illustrated by the
functionalization of product 6k (Scheme 2b). The remaining
iodide atom could be converted to other functional groups,
including alkenyl, alkynyl,16 phenyl,17 and hydroxyl18 groups
(7b−7e) by palladium or copper catalysts. A dehalogenation
reaction could also be carried out (7a).19
To gain preliminary mechanistic information about this
reaction, several control experiments were performed.
According to literature reports, aryl iodides can be conven-
iently oxidized with mCPBA to hypervalent iodosobenzene 8
or iodoxybenzene 9.15 To explore whether hypervalent
iodine(III) or iodine(V) played a role in the reaction process,
we individually reacted 8 and 9 with acetanilide 1k in HFIP for
6 h. Iodosobenzene 8 afforded the desired product 3k in a
relatively low yield (75%), but iodoxybenzene 9 failed. This
proved that the iodine atom was oxidized to form iodine(III)
intermediates (Scheme 3a). When p-iodotoluene 10 was
selected to participate in the reaction, as expected, the reaction
did not proceed (Scheme 3b), possibly because the key
intermediate A was not formed when the para-position was
blocked (Scheme 3b,c). In addition, a radical inhibition
experiment was performed in the presence of the radical
scavenger TEMPO, and the desired product 3k was obtained
in only a slightly lower yield, indicating that a radical pathway
was most likely not involved in this transformation (Scheme
3d), which was different from Li’s work.20 As we proposed, this
para C−H amination reaction might proceed via a nucleophilic
process rather than a radical process.
Based on our experimental observations, we suspected that
the HFIP solvent might play an important role in this reaction.
To validate the potential interactions between aniline,
iodobenzene, and HFIP, a set of NMR experiments were
designed with CDCl3 as the solvent (for details see the
Supporting Information). These results support the hydrogen
bonding between HFIP and the N atom of the acetanilide;
therefore, trivalent iodine may more easily combine with
oxygen than nitrogen.
8228
https://doi.org/10.1021/acs.joc.1c00681
J. Org. Chem. 2021, 86, 8226−8235

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
We also tracked the reaction between 1v and the same
amount of iodosobenzene 8 using NMR spectroscopy (Figure
1). Initially, the reaction was stirred at 0 °C for 1 h (Figure 1e).
zene 8 reacted with HFIP to form 11. Trivalent iodine
compound 11 combined with 1a to form intermediate B.
Afterward, B transformed into C, which activated the para-
position of iodobenzene and formed a carbocation. Sub-
sequently, carbocations were attacked by the nitrogen anions
to generate intermediate D. Finally, the desired product 3a was
obtained after re-aromatization of D.
3. CONCLUSIONS
In conclusion, we have developed a practical approach for the
synthesis of 4-iodo-N-phenylaniline derivatives by an oxida-
tion-induced method. A wide variety of anilines and
iodobenzenes were used in this study and were found to be
suitable for this reaction, producing the corresponding
products in moderate to good yields under mild conditions.
The direct conversion to products highlights the potential
synthetic applications of this method.
4. EXPERIMENTAL SECTION
4.1. General. Unless otherwise noted, all reagents were purchased
from commercial suppliers and used without further purification.
Column chromatography purifications were performed using 200−
300 mesh silica gel. NMR spectra were recorded on Varian Inova−
400 MHz, Inova−300 MHz, Bruker DRX−400, or Bruker DRX−500
instruments and calibrated using residual solvent peaks as internal
reference. Multiplicities are recorded as follows: s = singlet, d =
doublet, t = triplet, q = quartet, dd = doublet of doublets, td = triplet
of doublets, and m = multiplet. HRMS analysis was carried out using a
Bruker micrOTOF−Q instrument or a TOF−MS instrument.
4.1.1. General Procedure for the Compound (1j−1ab).23 A 100
mL round bottom flask was charged with aniline derivatives (20
mmol), CH2Cl2 (40 mL) and Et3N (4.0 mL, 28 mmol). Then, the
reaction solution was cooled to 0 °C. Acetyl chloride (1.7 mL, 24
mmol) was added dropwise. After addition, the solution was stirred at
room temperature for 10 h. Then, the reaction mixture was quenched
with water and extracted with CH2Cl2. The organic layer was dried
and concentrated, and the resulting residue was purified by column
chromatography (ethyl acetate/petroleum ether = 1:5) on silica gel to
provide N-phenylacetamide derivatives.
Figure 1. Tracking experiments by NMR spectroscopy.
We found that 8 quickly disappeared, and 11 (PhI(OC(H)-
(CF3)2)2) formed in HFIP (Figure 1c);21 thus, the amination
reaction failed. Then, we increased the temperature to 60 °C
(Figure 1f,g) and recorded the NMR spectrum. We observed
the gradual emergence of product 3v. To our surprise,
iodobenzene was also formed. We speculated that trivalent
iodine underwent a redox reaction with HFIP. To verify this
conjecture, 19F NMR analysis of the reaction mixture was
performed. Compared with the 19F NMR spectra of HFIP, a
new singlet at −82.6 ppm (s) appeared, which was known as
hexafluoroacetone (see the Supporting Information).22 There-
fore, it could be proved that HFIP participated in the redox
reaction.
4.1.2. General Procedure for the Compound (3j−3z, 3aa, and
3ab). A mixture of 1 (0.2 mmol, 1.0 equiv), 2 (0.4 mmol, 2.0 equiv),
mCPBA (0.4 mmol, 2.0 equiv), and HFIP (1.0 mL) in a 15 mL glass
vial sealed was maintained at 0 or 60 °C in an oil bath for 6 h. The
reaction mixture was concentrated in vacuo. The resulting residue was
purified by column chromatography (ethyl acetate/petroleum ether =
1:5) on silica gel to give the pure product.
Based on the results of the above experiments and a previous
literature survey, a plausible reaction pathway that was
different from Li’s is proposed in Scheme 4.20 First, 2a reacted
with mCPBA to produce iodosobenzene 8. Then, iodosoben-
Scheme 4. Proposed Mechanism
4.1.3. General Procedure for the Compound (5a−5l, 6j−6z, 6aa,
and 6ab). A mixture of 3 or 4 (0.2 mmol, 1.0 equiv), NaOH (1.0
mmol, 5.0 equiv) or K2CO3 (1.0 mmol, 5.0 equiv), and EtOH (10.0
mL) in a 50 mL round bottom flask was heated at 100 °C in an oil
bath for 1 h. The reaction mixture cooled to room temperature, and it
was filtered through a pad of celite and concentrated in vacuo. The
resulting residue was purified by column chromatography (ethyl
acetate/petroleum ether = 1:100) on silica gel to give the pure
product 5 or 6.
4.1.4. General Procedure for Gram-Scale Reaction. A mixture of
1u (4.7 mmol, 10.0 g), 2a (9.4 mmol, 2.0 equiv), mCPBA (9.4 mmol,
2.0 equiv), and HFIP (23.5 mL) in a 100 mL round bottomed flask
glass was cooled at 0 °C for 12 h. The reaction mixture was filtered
through a pad of celite and concentrated in vacuo. The resulting
residue was purified by column chromatography (ethyl acetate/
petroleum ether = 1:5) on silica gel to give the pure product 3u (13.8
g).
4.1.5. General Procedure for the Synthesis of Compounds 7a. A
mixture of 6k (0.2 mmol, 1.0 equiv), NaBH4 (3.0 mmol, 15 equiv),
CuCl (75 mol %), and MeOH (2.0 mL) in a 15 mL glass vial sealed
was cooled at 0 °C for 1 h. The reaction mixture was filtered through
a pad of celite and concentrated in vacuo. The resulting residue was
8229
https://doi.org/10.1021/acs.joc.1c00681
J. Org. Chem. 2021, 86, 8226−8235

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
purified by column chromatography (ethyl acetate/petroleum ether =
1:100) on silica gel to give the pure product 7a.
128.3, 126.7, 90.8, 24.0. HRMS (ESI) m/z: [M + Na]+ Calcd for
C14H12INONa: 359.9861; found: 359.9871.
N-(2-Chlorophenyl)-N-(4-iodophenyl)acetamide (3k) The com-
pound was purified by flash column chromatography (ethyl acetate/
petroleum ether = 1:5) to give the product as yellow oil; yield: 60.8
mg, 82%. 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 2H), 7.51 (s, 1H),
7.35 (s, 3H), 7.08 (d, J = 8.2 Hz, 2H), 2.00 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ 170.2, 141.1, 140.0, 137.9, 133.7, 131.0, 130.1,
128.5, 127.7, 90.8, 23.5. HRMS (ESI) m/z: [M + Na]+ Calcd for
C14H11ClINONa: 393.9472; found: 393.9477.
4.1.6. General Procedure for the Synthesis of Compounds 7b. A
mixture of 6k (0.2 mmol, 1.0 equiv), ethyl acrylate (0.4 mmol, 2.0
equiv), Pd(OAc)2 (10 mol %), PPh3 (5 mol %), and Et3N (0.5 mL) in
a 15 mL glass vial sealed was stirred at 100 °C in an oil bath for 24 h.
The reaction mixture was filtered through a pad of celite and
concentrated in vacuo. The resulting residue was purified by column
chromatography (ethyl acetate/petroleum ether = 1:100) on silica gel
to give the pure product 7b.
4.1.7. General Procedure for the Synthesis of Compounds 7c. A
mixture of 6k (0.2 mmol, 1.0 equiv), phenylacetylene (0.4 mmol, 2.0
equiv), Pd(PPh3)4 (5 mol %), CuI (10 mol %), and Et3N (0.5 mL) in
a 15 mL glass vial sealed was stirred at 100 °C in an oil bath for 24 h.
The reaction mixture was filtered through a pad of celite and
concentrated in vacuo. The resulting residue was purified by column
chromatography (ethyl acetate/petroleum ether = 1:100) on silica gel
to give the pure product 7c.
4.1.8. General Procedure for the Synthesis of Compounds 7d. A
mixture of 6k (0.2 mmol, 1.0 equiv), phenylboronic acid (0.4 mmol,
2.0 equiv), Pd(OAc)2 (10 mol %), K3PO4 (2.0 equiv), xantphos (20
mol %), and Et3N (0.5 mL) in a 15 mL glass vial sealed was stirred at
100 °C in an oil bath for 16 h under nitrogen. The reaction mixture
was filtered through a pad of celite and concentrated in vacuo. The
resulting residue was purified by column chromatography (ethyl
acetate/petroleum ether = 1:100) on silica gel to give the pure
product 7d.
4.1.9. General Procedure for the Synthesis of Compounds 7e. A
mixture of 6k (0.2 mmol, 1.0 equiv), CuI (10 mol %), KOH (5.0
equiv), Phen (20 mol %), and DMSO/H2O (0.25 mL:0.25 mL) in a
15 mL glass vial sealed was stirred at 120 °C in an oil bath for 24 h
under nitrogen. The reaction mixture was filtered through a pad of
celite and extracted with ethyl acetate concentrated. The resulting
residue was concentrated in vacuo and purified by column
chromatography (ethyl acetate/petroleum ether = 1:5) on silica gel
to give the pure product 7e.
N-(2-Bromophenyl)-N-(4-iodophenyl)acetamide (3l) The compound
was purified by flash column chromatography (ethyl acetate/
petroleum ether = 1:5) to give the product as yellow oil; yield:
1
72.2 mg, 87%. H NMR (400 MHz, CDCl3) δ 7.81−7.52 (m, 3H),
7.39 (s, 2H), 7.26 (s, 1H), 7.12 (d, J = 8.3 Hz, 2H), 2.00 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 169.8, 141.3, 140.8, 137.5,
134.2, 131.0, 130.1, 129.1, 127.3, 124.1, 90.4, 23.7. HRMS (ESI) m/z:
[M + Na]+ Calcd for C14H11BrINONa: 437.8966; found: 437.8960.
N-([1,1′-Biphenyl]-3-yl)-N-(4-iodophenyl)acetamide (3m) The com-
pound was purified by flash column chromatography (ethyl acetate/
petroleum ether = 1:5) to give the product as yellow oil; yield: 38.8
mg, 47%. 1H NMR (400 MHz, CDCl3) δ 7.78−7.63 (m, 2H), 7.62−
7.43 (m, 6H), 7.42−7.38 (m, 1H), 7.28−7.25 (m, 1H), 7.10 (d, J =
8.2 Hz, 2H), 2.14 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
170.3, 143.1, 142.6, 139.7, 138.1, 130.1, 128.9, 127.9, 127.1, 90.8,
24.0. HRMS (ESI) m/z: [M + Na]+ Calcd for C20H16INONa:
436.0174; found: 436.0179.
N-(3-Fluorophenyl)-N-(4-iodophenyl)acetamide (3n) The compound
was purified by flash column chromatography (ethyl acetate/
petroleum ether = 1:5) to give the product as yellow oil; yield:
1
51.7 mg, 73%. H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.1 Hz,
2H), 7.30 (s, 1H), 7.05−6.82 (m, 5H), 2.04 (s, 3H). 19F NMR (376
MHz, CDCl3) δ −112.0. 13C{1H} NMR (100 MHz, CDCl3) δ 170.1,
164.1, 161.6, 143.9, 142.3, 130.5, 124.2, 122.5, 114.5, 92.1, 23.9.
HRMS (ESI) m/z: [M + Na]+ Calcd for C14H11FINONa: 377.9767;
found: 377.9770.
N-(3-Chlorophenyl)-N-(4-iodophenyl)acetamide (3o) The com-
pound was purified by flash column chromatography (ethyl acetate/
petroleum ether = 1:5) to give the product as yellow oil; yield: 51.9
mg, 70%. 1H NMR (400 MHz, CDCl3) δ 7.70 (s, 2H), 7.39−7.17 (m,
3H), 7.14 (d, J = 7.0 Hz, 1H), 7.04−6.97 (m, 2H), 2.06 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 170.0, 143.6, 142.3, 138.6,
134.9, 130.3, 128.3, 126.8, 124.7, 23.9. HRMS (ESI) m/z: [M + Na]+
Calcd for C14H11ClINONa: 393.9472; found: 393.9476.
N-(3-Bromophenyl)-N-(4-iodophenyl)acetamide (3p) The com-
pound was purified by flash column chromatography (ethyl acetate/
petroleum ether = 1:5) to give the product as yellow oil; yield: 66.4
mg, 80%. 1H NMR (400 MHz, CDCl3) δ 7.69 (s, 2H), 7.41 (s, 2H),
7.19 (s, 2H), 7.00 (d, J = 8.2 Hz, 2H), 2.05 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ 169.9, 143.7, 142.2, 138.6, 130.6, 129.8, 126.9,
125.3, 122.7, 23.8. HRMS (ESI) m/z: [M + Na]+ Calcd for
C14H11BrINONa: 437.8966; found: 437.8967.
Methyl 3-(N-(4-iodophenyl)acetamido)benzoate (3q) The com-
pound was purified by flash column chromatography (ethyl acetate/
petroleum ether = 1:5) to give the product as yellow oil; yield: 60.0
mg, 76%. 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 2H), 7.59 (s, 2H),
7.38 (s, 2H), 7.01−6.92 (m, 2H), 3.79 (s, 3H), 1.97 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 169.5, 165.5, 142.4, 142.0, 138.1, 131.1,
129.0, 93.0, 90.8, 51.9, 23.4. HRMS (ESI) m/z: [M + Na]+ Calcd for
C16H14INO3Na: 417.9916; found: 417.9920.
N-(4-Iodophenyl)-4-methyl-N-phenylbenzenesulfonamide (3f) The
compound was purified by flash column chromatography (ethyl
acetate/petroleum ether = 1:5) to give the product as a white solid,
m.p. 159−160 °C; yield: 7.2 mg, 8%. 1H NMR (400 MHz, CDCl3) δ
7.64−7.60 (m, 2H), 7.58−7.56 (m, 2H), 7.35−7.26 (m, 5H), 7.24−
7.20 (m, 2H), 7.04−6.99 (m, 2H), 2.44 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ 143.9, 141.5, 141.1, 138.4, 137.3, 129.8, 129.7, 129.4,
128.4, 127.8, 127.7, 92.4, 21.6. HRMS (ESI) m/z: [M + Na]+ Calcd
for C19H16INO2SNa 471.9844; found: 471.9856.
N-(4-Iodophenyl)-N-phenylbenzamide (3h) The compound was
purified by flash column chromatography (ethyl acetate/petroleum
ether = 1:5) to give the product as a white solid, m.p. 124−126 °C;
1
yield: 18.3 mg, 23%. H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.7
Hz, 2H), 7.48−7.41 (m, 2H), 7.37−7.26 (m, 3H), 7.24−7.17 (m,
3H), 7.13−7.08 (m, 2H), 6.91 (d, J = 8.6 Hz, 2H). 13C{1H} NMR
(100 MHz, CDCl3) δ 170.6, 143.8, 143.6, 138.3, 135.8, 130.6, 129.4,
129.3, 129.2, 128.1, 127.7, 126.8, 91.1. HRMS (ESI) m/z: [M + Na]+
Calcd for C19H14INONa 422.0018; found: 422.0022.
2,2,2-Trifluoro-N-(4-iodophenyl)-N-phenylacetamide (3i) The com-
pound was purified by flash column chromatography (ethyl acetate/
petroleum ether = 1:5) to give the product as a white solid, m.p. 74−
75 °C; yield: 25.8 mg, 33%. 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J
= 8.3 Hz, 2H), 7.44−7.31 (m, 5H), 7.08 (d, J = 8.2 Hz, 2H). 19F
NMR (376 MHz, CDCl3) δ −66.8. 13C{1H} NMR (100 MHz,
CDCl3) δ 156.4 (q, J = 36.2 Hz), 138.7, 130.5, 129.7, 129.4, 128.7,
127.9, 126.1, 116.3 (q, JC‑F = 288.9 Hz), 92.7. HRMS (ESI) m/z: [M
+ Na]+ Calcd for C14H9F3INONa 413.9579; found: 413.9588.
N-(4-Iodophenyl)-N-phenylacetamide (3j) The compound was
purified by flash column chromatography (ethyl acetate/petroleum
ether = 1:5) to give the product as a white solid, m.p. 93−94 °C;
N-(3-Acetylphenyl)-N-(4-iodophenyl)acetamide (3r) The compound
was purified by flash column chromatography (ethyl acetate/
petroleum ether = 1:5) to give the product as yellow oil; yield:
1
39.4 mg, 52%. H NMR (400 MHz, CDCl3) δ 7.79 (s, 2H), 7.63 (s,
2H), 7.41 (s, 2H), 6.98 (d, J = 8.2 Hz, 2H), 2.52 (s, 3H), 2.00 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ 196.9, 169.9, 142.8, 142.2,
138.4, 129.7, 126.3, 93.2, 26.6, 23.6. HRMS (ESI) m/z: [M + Na]+
Calcd for C16H14INO2Na: 401.9967; found: 401.9968.
1
yield: 57.96 mg, 86%. H NMR (400 MHz, CDCl3) δ 7.57 (s, 2H),
7.31−7.24 (m, 3H), 7.17−7.14 (m, 2H), 6.97−6.91 (m, 2H), 1.97 (s,
N-(4-Iodophenyl)-N-(3-(trifluoromethyl)phenyl)acetamide (3s) The
compound was purified by flash column chromatography (ethyl
3H). 13C{1H} NMR (100 MHz, CDCl3) δ 170.4, 142.8, 138.2, 129.9,
8230
https://doi.org/10.1021/acs.joc.1c00681
J. Org. Chem. 2021, 86, 8226−8235

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1
acetate/petroleum ether = 1:5) to give the product as yellow oil;
yield: 51.8 mg, 64%. H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.1
yield: 59.2 mg, 69%. H NMR (400 MHz, CDCl3) δ 7.62 (s, 2H),
7.40 (s, 2H), 7.17 (d, J = 8.2 Hz, 1H), 6.99 (d, J = 8.3 Hz, 2H), 2.16
(s, 3H), 1.98 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 169.9,
142.4, 137.9, 135.3, 133.2, 132.5, 126.8, 120.1, 23.9, 17.6. HRMS
(ESI) m/z: [M + Na]+ Calcd for C15H13BrINONa: 451.9123; found:
451.9133.
1
Hz, 2H), 7.59−7.37 (m, 4H), 7.01 (d, J = 8.6 Hz, 2H), 2.06 (s, 3H).
19F NMR (376 MHz, CDCl3) δ −62.6. 13C{1H} NMR (100 MHz,
CDCl3) δ 170.2, 143.0, 142.3, 139.0, 130.0, 125.0, 123.6, 122.3, 23.9.
HRMS (ESI) m/z: [M + Na]+ Calcd for C15H11F3INONa: 427.9735;
found: 427.9739.
N-(3,4-Difluorophenyl)-N-(4-iodophenyl)acetamide (3ab) The com-
pound was purified by flash column chromatography (ethyl acetate/
petroleum ether = 1:5) to give the product as yellow oil; yield: 60.4
mg, 81%. 1H NMR (400 MHz, CDCl3) δ 7.69 (s, 2H), 7.19−7.04 (m,
2H), 7.02−6.92 (m, 3H), 2.03 (s, 3H). 19F NMR (376 MHz, CDCl3)
δ −133.4, −135.6, −136.6, −139.9. 13C{1H} NMR (100 MHz,
CDCl3) δ 169.9, 151.2, 148.7, 142.1, 138.7, 130.0, 128.2, 124.7, 122.4,
117.4, 115.9, 93.4, 91.3, 23.6. HRMS (ESI) m/z: [M + Na]+ Calcd for
C14H10F2INONa: 395.9673; found: 395.9677.
N-(4-Chlorophenyl)-N-(4-iodophenyl)acetamide (3t) The compound
was purified by flash column chromatography (ethyl acetate/
petroleum ether = 1:5) to give the product as yellow oil; yield:
1
66.0 mg, 89%. H NMR (400 MHz, CDCl3) δ 7.69 (s, 2H), 7.34 (s,
2H), 7.17 (d, J = 8.5 Hz, 2H), 6.99 (d, J = 8.6 Hz, 2H), 2.05 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 170.2, 142.5, 141.2, 138.7,
129.8, 128.4, 23.9. HRMS (ESI) m/z: [M + Na]+ Calcd for
C14H11ClINONa: 393.9472; found: 393.9471.
N-(4-Bromophenyl)-N-(4-iodophenyl)acetamide (3u) The com-
pound was purified by flash column chromatography (ethyl acetate/
petroleum ether = 1:5) to give the product as yellow oil; yield: 69.7
mg, 84%. 1H NMR (400 MHz, CDCl3) δ 7.66 (s, 2H), 7.47 (s, 2H),
7.10 (d, J = 8.1 Hz, 2H), 6.98 (d, J = 8.1 Hz, 2H), 2.03 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 170.0, 142.3, 141.6, 138.6,
132.6, 130.0, 128.2, 23.9. HRMS (ESI) m/z: [M + Na]+ Calcd for
C14H11BrINONa: 437.8966; found: 437.8966.
N-(2-Chlorophenyl)-4-iodo-3-methylaniline (5a) The compound was
purified by flash column chromatography (ethyl acetate/petroleum
ether = 1:100) to give the product as colorless oil; yield: 48.1 mg,
1
70%. H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.4 Hz, 1H), 7.41
(dd, J = 8.0, 1.5 Hz, 1H), 7.30 (dd, J = 8.2, 1.6 Hz, 1H), 7.21−7.16
(m, 1H), 7.06 (d, J = 2.8 Hz, 1H), 6.88 (td, J = 7.7, 1.6 Hz, 1H), 6.74
(dd, J = 8.5, 2.8 Hz, 1H), 6.06 (s, 1H), 2.44 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ 142.4, 141.9, 139.6, 139.5, 129.9, 127.5, 122.1,
121.0, 121.0, 118.7, 116.2, 91.6, 28.2. HRMS (ESI) m/z: [M + H]+
Calcd for C13H12ClIN 343.9703; found: 343.9691.
Ethyl 4-(N-(4-iodophenyl)acetamido)benzoate (3v) The compound
was purified by flash column chromatography (ethyl acetate/
petroleum ether = 1:5) to give the product as yellow oil; yield:
N-(2-Chlorophenyl)-3-ethyl-4-iodoaniline (5b) The compound was
purified by flash column chromatography (ethyl acetate/petroleum
ether = 1:100) to give the product as colorless oil; yield: 49.2 mg,
1
49.1 mg, 60%. H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.2 Hz,
2H), 7.67 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.6 Hz, 2H), 6.98 (d, J =
8.6 Hz, 2H), 4.32 (q, J = 7.1 Hz, 2H), 2.03 (s, 3H), 1.34 (t, J = 7.1
Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 169.8, 165.5, 146.3,
142.1, 138.6, 129.5, 128.6, 126.6, 92.5, 61.0, 24.0, 14.2. HRMS (ESI)
m/z: [M + Na]+ Calcd for C17H16INO3Na: 432.0073; found:
432.0077.
1
69%. H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.5 Hz, 1H), 7.39
(dd, J = 8.0, 1.5 Hz, 1H), 7.28 (dd, J = 8.2, 1.5 Hz, 1H), 7.19−7.15
(m, 1H), 7.05 (d, J = 2.8 Hz, 1H), 6.88−6.84 (m, 1H), 6.75 (dd, J =
8.4, 2.8 Hz, 1H), 2.72 (q, J = 7.5 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 147.7, 142.2, 140.0, 139.7,
129.9, 127.6, 122.1, 121.0, 120.0, 119.0, 116.1, 90.9, 34.2, 14.6.
HRMS (ESI) m/z: [M + H]+ Calcd for C14H14ClIN 357.9859; found:
357.9861.
N-(2-Iodophenyl)-N-(4-iodophenyl)acetamide (3w) The compound
was purified by flash column chromatography (ethyl acetate/
petroleum ether = 1:5) to give the product as yellow oil; yield:
1
57.4 mg, 62%. H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.0 Hz,
N-(2-Chlorophenyl)-4-iodo-3-isopropylaniline (5c) The compound
was purified by flash column chromatography (ethyl acetate/
petroleum ether = 1:100) to give the product as colorless oil; yield:
1H), 7.60 (s, 2H), 7.40 (d, J = 17.3 Hz, 4H), 7.11 (d, J = 8.5 Hz, 3H),
1.98 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 169.7, 144.6,
140.7, 137.5, 130.6, 130.0, 127.3, 100.7, 90.2, 24.4. HRMS (ESI) m/z:
[M + Na]+ Calcd for C14H11I2NONa: 485.8828; found: 485.8829.
N-(3-Iodophenyl)-N-(4-iodophenyl)acetamide (3x) The compound
was purified by flash column chromatography (ethyl acetate/
petroleum ether = 1:5) to give the product as yellow oil; yield:
1
50.4 mg, 68%. H NMR (400 MHz, CDCl3) δ 7.72 (dd, J = 8.4, 1.3
Hz, 1H), 7.38 (dt, J = 8.1, 1.5 Hz, 1H), 7.27−7.23 (m, 1H), 7.15 (tt, J
= 8.4, 1.4 Hz, 1H), 7.05 (t, J = 2.6 Hz, 1H), 6.86−6.80 (m, 1H),
6.78−6.75 (m, 1H), 6.09 (s, 1H), 3.22−3.15 (m, 1H), 1.25 (dd, J =
6.8, 2.2 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 151.7, 142.3,
140.1, 139.8, 130.0, 127.6, 122.0, 120.9, 119.3, 117.9, 115.9, 91.7,
38.1, 23.2. HRMS (ESI) m/z: [M + H]+ Calcd for C15H16ClIN
372.0016; found: 372.0011.
N-(2-Chlorophenyl)-3-fluoro-4-iodoaniline (5d) The compound was
purified by flash column chromatography (ethyl acetate/petroleum
ether = 1:100) to give the product as colorless oil; yield: 31.9 mg,
46%. 1H NMR (400 MHz, CDCl3) δ 7.60−7.56 (m, 1H), 7.39 (dd, J
= 8.0, 1.5 Hz, 1H), 7.31 (dd, J = 8.2, 1.5 Hz, 1H), 7.19 (td, J = 8.2,
7.8, 1.5 Hz, 1H), 6.92 (td, J = 7.7, 1.5 Hz, 1H), 6.87 (dd, J = 9.9, 2.5
Hz, 1H), 6.68 (dd, J = 8.5, 2.6 Hz, 1H), 6.11 (s, 1H). 19F NMR (376
MHz, CDCl3) δ −92.73 − −92.78 (m). 13C{1H} NMR (100 MHz,
CDCl3) δ 162.5 (d, JC‑F = 244.2 Hz), 144.4 (d, JC‑F = 9.6 Hz), 139.6
(d, JC‑F = 3.3 Hz), 138.6, 130.2, 127.7, 123.4, 122.5, 117.8, 116.2 (d,
JC‑F = 3.0 Hz), 105.7 (d, JC‑F = 27.4 Hz), 70.2 (d, JC‑F = 25.9 Hz).
HRMS (ESI) m/z: [M + H]+ Calcd for C12H9ClFIN 347.9452;
found: 347.9457.
1
47.2 mg, 51%. H NMR (400 MHz, CDCl3) δ 7.67 (s, 2H), 7.59 (s,
2H), 7.20 (d, J = 8.0 Hz, 1H), 7.07 (s, 1H), 7.02−6.95 (m, 2H), 2.03
(s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 169.9, 143.5, 142.1,
138.5, 137.0, 130.8, 130.7, 94.3, 23.8. HRMS (ESI) m/z: [M + Na]+
Calcd for C14H11I2NONa: 485.8828; found: 485.8825.
N-(4-Iodophenyl)-N-(3-isopropylphenyl)acetamide (3y) The com-
pound was purified by flash column chromatography (ethyl acetate/
petroleum ether = 1:5) to give the product as yellow oil; yield: 54.6
1
mg, 72%. H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.4 Hz, 2H),
7.31 (t, J = 7.8 Hz, 1H), 7.19 (s, 1H), 7.09 (t, J = 1.9 Hz, 1H), 7.06−
7.00 (m, 3H), 2.93−2.86 (m, 1H), 2.04 (s, 3H), 1.23 (d, J = 7.0 Hz,
6H). 13C{1H} NMR (100 MHz, CDCl3) δ 170.3, 151.0, 142.7, 138.0,
129.6, 128.1, 126.0, 125.7, 90.5, 33.9, 24.0, 23.9. HRMS (ESI) m/z:
[M + Na]+ Calcd for C17H18INONa: 402.0331; found: 402.0333.
N-(3-Chloro-4-methylphenyl)-N-(4-iodophenyl)acetamide (3z) The
compound was purified by flash column chromatography (ethyl
acetate/petroleum ether = 1:5) to give the product as yellow oil;
1
N-(2-Chlorophenyl)-4-iodo-3-(trifluoromethyl)aniline (5e) The com-
pound was purified by flash column chromatography (ethyl acetate/
petroleum ether = 1:100) to give the product as colorless oil; yield:
yield: 50.0 mg, 65%. H NMR (400 MHz, CDCl3) δ 7.64 (s, 2H),
7.26−7.17 (m, 2H), 7.06−7.03 (m, 1H), 7.02−6.96 (m, 2H), 2.33 (s,
3H), 2.03 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 169.8, 142.2,
141.1, 138.2, 136.0, 134.6, 131.4, 129.8, 128.2, 126.6, 124.8, 92.9,
90.8, 23.6, 19.5. HRMS (ESI) m/z: [M + Na]+ Calcd for
C15H13ClINONa: 407.9628; found: 407.9629.
N-(5-Bromo-2-methylphenyl)-N-(4-iodophenyl)acetamide (3aa) The
compound was purified by flash column chromatography (ethyl
acetate/petroleum ether = 1:5) to give the product as yellow oil;
1
17.4 mg, 22%. H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.5 Hz,
1H), 7.41 (dd, J = 8.0, 1.6 Hz, 2H), 7.28 (dd, J = 8.2, 1.6 Hz, 1H),
7.20 (td, J = 8.3, 7.8, 1.5 Hz, 1H), 6.99−6.91 (m, 2H), 6.14 (s, 1H).
19F NMR (376 MHz, CDCl3) δ −63.00. 13C{1H} NMR (100 MHz,
CDCl3) δ 142.8, 142.6, 138.4, 134.6 (q, JC‑F = 30.9 Hz), 130.3, 127.8,
123.6, 122.8, 122.7 (q, JC‑F = 272.5 Hz), 122.2, 117.8 (q, JC‑F = 5.7
8231
https://doi.org/10.1021/acs.joc.1c00681
J. Org. Chem. 2021, 86, 8226−8235

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Hz), 117.7, 79.6 (q, JC‑F = 1.9 Hz). HRMS (ESI) m/z: [M + H]+
Calcd for C13H9ClF3IN 397.9420; found: 397.9420.
1H), 6.91 (s, 2H), 6.84 (td, J = 7.6, 1.6 Hz, 1H), 5.99 (s, 1H), 2.46 (s,
6H). 13C{1H} NMR (100 MHz, CDCl3) δ 143.1, 141.3, 139.9, 129.9,
127.6, 122.1, 120.9, 118.4, 116.4, 99.1, 29.8. HRMS (ESI) m/z: [M +
H]+ Calcd for C14H14ClIN 357.9859; found: 357.9871.
3-Bromo-N-(2-chlorophenyl)-4-iodoaniline (5f) The compound was
purified by flash column chromatography (ethyl acetate/petroleum
ether = 1:100) to give the product as colorless oil; yield: 47.2 mg,
4-Iodo-N-phenylaniline (6j) The compound was purified by flash
column chromatography (ethyl acetate/petroleum ether = 1:100) to
give the product as a white solid, m.p. 102−103 °C; yield: 45.4 mg,
77%. 1H NMR (400 MHz, CDCl3) δ 7.61−7.53 (m, 2H), 7.39−7.31
(m, 2H), 7.14−7.08 (m, 2H), 7.05 (tt, J = 7.3, 1.1 Hz, 1H), 6.89−
6.82 (m, 2H), 5.69 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ
143.1, 142.1, 138.0, 129.5, 121.8, 119.3, 118.5, 82.2. HRMS (ESI) m/
z: [M + H]+ Calcd for C12H11IN 295.9936; found: 295.9951.
2-Chloro-N-(4-iodophenyl)aniline (6k) The compound was purified
by flash column chromatography (ethyl acetate/petroleum ether =
1:100) to give the product as a white solid, m.p. 70−71 °C; yield: 50.0
1
58%. H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.6 Hz, 1H), 7.41
(d, J = 2.6 Hz, 1H), 7.38 (dd, J = 8.0, 1.5 Hz, 1H), 7.28 (dd, J = 8.2,
1.6 Hz, 1H), 7.21−7.16 (m, 1H), 6.93−6.89 (m, 1H), 6.78 (dd, J =
8.6, 2.6 Hz, 1H), 6.04 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ
143.4, 140.6, 138.6, 130.4, 130.2, 127.7, 123.2, 122.5, 122.3, 119.1,
117.5, 90.4. HRMS (ESI) m/z: [M + H]+ Calcd for C12H9BrClIN
407.8652; found: 407.8636.
N-(2-Chlorophenyl)-3-(ethoxymethyl)-4-iodoaniline (5g) The com-
pound was purified by flash column chromatography (ethyl acetate/
petroleum ether = 1:100) to give the product as colorless oil; yield:
1
1
38.7 mg, 50%. H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.4 Hz,
mg, 76%. H NMR (400 MHz, CDCl3) δ 7.56−7.51 (m, 2H), 7.33
1H), 7.27 (dd, J = 8.0, 1.5 Hz, 1H), 7.21−7.14 (m, 2H), 7.07−7.03
(m, 1H), 6.78−6.71 (m, 2H), 6.01 (s, 1H), 4.35 (s, 2H), 3.55 (q, J =
7.0 Hz, 2H), 1.20 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 142.3, 142.0, 139.7, 139.5, 129.9, 127.6, 122.3, 121.2, 119.8,
119.7, 116.4, 87.4, 76.2, 66.5, 15.4. HRMS (ESI) m/z: [M + H]+
Calcd for C15H16ClINO 387.9965; found: 387.9964.
(dd, J = 8.0, 1.5 Hz, 1H), 7.21 (dd, J = 8.2, 1.5 Hz, 1H), 7.10 (td, J =
8.2, 7.8, 1.5 Hz, 1H), 6.88−6.83 (m, 2H), 6.81−6.79 (m, 1H), 6.01
(s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 141.5, 139.4, 138.3,
129.9, 127.6, 122.3, 121.5, 121.3, 116.3, 84.5. HRMS (ESI) m/z: [M
+ H]+ Calcd for C12H10ClIN 329.9546; found: 329.9547.
2-Bromo-N-(4-iodophenyl)aniline (6l) The compound was purified
by flash column chromatography (ethyl acetate/petroleum ether =
1:100) to give the product as a white solid, m.p. 62−63 °C; yield: 53.7
N-(2-Chlorophenyl)-4-iodo-2-methylaniline (5h) The compound was
purified by flash column chromatography (ethyl acetate/petroleum
ether = 1:100) to give the product as colorless oil; yield: 45.3 mg,
1
mg, 72%. H NMR (400 MHz, CDCl3) δ 7.61−7.56 (m, 2H), 7.54
1
66%. H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 2.1 Hz, 1H), 7.39
(dd, J = 8.0, 1.5 Hz, 1H), 7.24 (dd, J = 8.2, 1.8 Hz, 1H), 7.21−7.16
(m, 1H), 6.94−6.87 (m, 2H), 6.81−6.77 m, 1H), 6.03 (s, 1H).
13C{1H} NMR (100 MHz, CDCl3) δ 141.7, 140.6, 138.4, 133.2,
128.3, 121.9, 121.6, 116.7, 113.0, 84.6. HRMS (ESI) m/z: [M + H]+
Calcd for C12H10BrIN 373.9041; found: 373.9050.
(dd, J = 8.4, 2.1 Hz, 1H), 7.29 (dd, J = 8.0, 1.5 Hz, 1H), 7.04 (ddd, J
= 8.6, 7.3, 1.5 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.87 (dd, J = 8.2, 1.5
Hz, 1H), 6.73 (td, J = 7.6, 1.5 Hz, 1H), 5.73 (s, 1H), 2.15 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 140.3, 139.7, 139.7, 135.8,
133.0, 129.8, 127.6, 122.9, 121.6, 120.5, 115.8, 86.6, 17.6. HRMS
(ESI) m/z: [M + H]+ Calcd for C13H12ClIN 343.9703; found:
343.9691.
N-(4-Iodophenyl)-[1,1′-biphenyl]-3-amine (6m) The compound was
purified by flash column chromatography (ethyl acetate/petroleum
ether = 1:100) to give the product as a white solid, m.p. 92−93 °C;
5-Bromo-N-(2-chlorophenyl)-4-iodo-2-methylaniline (5i) The com-
pound was purified by flash column chromatography (ethyl acetate/
petroleum ether = 1:100) to give the product as colorless oil; yield:
1
yield: 31.2 mg, 42%. H NMR (400 MHz, CDCl3) δ 7.56 (m, 4H),
7.47−7.41 (m, 2H), 7.40−7.33 (m, 2H), 7.29 (t, J = 2.0 Hz, 1H),
7.21 (dt, J = 7.7, 1.3 Hz, 1H), 7.05 (m, 1H), 6.92−6.85 (m, 2H), 5.77
(s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 143.1, 142.8, 142.8,
141.0, 138.3, 130.0, 128.9, 127.6, 127.2, 120.8, 119.6, 117.4, 117.2,
82.5. HRMS (ESI) m/z: [M + H]+ Calcd for C18H15IN 372.0249;
found: 372.0264.
3-Fluoro-N-(4-iodophenyl)aniline (6n) The compound was purified
by flash column chromatography (ethyl acetate/petroleum ether =
1:100) to give the product as a white solid, m.p. 98−99 °C; yield: 38.8
mg, 62%. 1H NMR (400 MHz, CDCl3) δ 7.59−7.53 (m, 2H), 7.23−
7.17 (m, 1H), 6.88−6.83 (m, 2H), 6.80−6.73 (m, 2H), 6.65−6.60
(m, 1H), 5.75 (s, 1H). 19F NMR (376 MHz, CDCl3) δ −111.81.
13C{1H} NMR (100 MHz, CDCl3) δ 163.8 (d, JC‑F = 244.8 Hz),
144.5 (d, JC‑F = 10.4 Hz), 142.1, 138.4, 130.7 (d, JC‑F = 9.9 Hz), 120.5,
113.3, 108.0 (d, JC‑F = 21.4 Hz), 104.4 (d, JC‑F = 24.9 Hz), 83.7.
HRMS (ESI) m/z: [M + H]+ Calcd for C12H10FIN 313.9842; found:
313.9838.
3-Chloro-N-(4-iodophenyl)aniline (6o) The compound was purified
by flash column chromatography (ethyl acetate/petroleum ether =
1:100) to give the product as a white solid, m.p. 82−83 °C; yield: 40.1
mg, 61%. 1H NMR (400 MHz, CDCl3) δ 7.58−7.53 (m, 2H), 7.18 (t,
J = 8.0 Hz, 1H), 7.03 (t, J = 2.1 Hz, 1H), 6.93−6.87 (m, 2H), 6.87−
6.82 (m, 2H), 5.69 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ
144.0, 142.1, 138.4, 135.2, 130.6, 121.4, 120.5, 117.5, 115.9, 83.8.
HRMS (ESI) m/z: [M + H]+ Calcd for C12H10ClIN 329.9546; found:
329.9555.
3-Bromo-N-(4-iodophenyl)aniline (6p) The compound was purified
by flash column chromatography (ethyl acetate/petroleum ether =
1:100) to give the product as a white solid, m.p. 85−86 °C; yield: 53.7
mg, 72%. 1H NMR (400 MHz, CDCl3) δ 7.59−7.53 (m, 2H), 7.18 (t,
J = 2.0 Hz, 1H), 7.12 (t, J = 7.9 Hz, 1H), 7.08−7.05 (m, 1H), 6.94
(ddd, J = 7.9, 2.2, 1.1 Hz, 1H), 6.86−6.80 (m, 2H), 5.68 (s, 1H).
13C{1H} NMR (100 MHz, CDCl3) δ 144.0, 142.0, 138.3, 130.8,
124.3, 123.2, 120.4, 120.4, 116.3, 83.8. HRMS (ESI) m/z: [M + H]+
Calcd for C12H10BrIN 373.9041; found: 373.9046.
1
52.2 mg, 62%. H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 1.0 Hz,
1H), 7.49 (s, 1H), 7.39 (dd, J = 8.0, 1.5 Hz, 1H), 7.20−7.16 (m, 1H),
7.08 (dd, J = 8.2, 1.6 Hz, 1H), 6.89 (td, J = 7.6, 1.6 Hz, 1H), 5.82 (s,
1H), 2.20 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 141.61,
141.45, 139.12, 130.11, 129.86, 127.69, 127.09, 122.77, 122.41,
121.57, 116.90, 92.01, 17.10. HRMS (ESI) m/z: [M + H]+ Calcd for
C13H11BrClIN 421.8808; found: 421.8820.
N-(2-Chlorophenyl)-4-iodo-2,3-dimethylaniline (5j) The compound
was purified by flash column chromatography (ethyl acetate/
petroleum ether = 1:100) to give the product as colorless oil; yield:
1
47.1 mg, 66%. H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.4 Hz,
1H), 7.35 (dd, J = 8.0, 1.5 Hz, 1H), 7.12−7.05 (m, 1H), 6.85 (d, J =
8.4 Hz, 1H), 6.80−6.71 (m, 2H), 5.85 (s, 1H), 2.52 (s, 3H), 2.28 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ 141.4, 140.7, 139.8, 137.0,
132.3, 129.6, 127.6, 123.0, 120.6, 119.7, 114.9, 96.9, 26.3, 15.9.
HRMS (ESI) m/z: [M + H]+ Calcd for C14H14ClIN 357.9859; found:
357.9864.
N-(2-Chlorophenyl)-2-fluoro-4-iodo-3-methylaniline (5k) The com-
pound was purified by flash column chromatography (ethyl acetate/
petroleum ether = 1:100) to give the product as colorless oil; yield:
1
36.8 mg, 51%. H NMR (400 MHz, CDCl3) δ 7.48 (dd, J = 8.6, 1.6
Hz, 1H), 7.39 (dd, J = 7.9, 1.5 Hz, 1H), 7.24 (dd, J = 8.2, 1.6 Hz,
1H), 7.17 (td, J = 8.2, 7.7, 1.5 Hz, 1H), 6.96−6.87 (m, 2H), 6.09 (s,
1H), 2.39 (d, J = 2.8 Hz, 3H). 19F NMR (376 MHz, CDCl3) δ
−127.1. 13C{1H} NMR (100 MHz, CDCl3) δ 151.3 (d, JC‑F = 244.8
Hz), 138.7, 133.7 (d, JC‑F = 4.3 Hz), 130.5 (d, JC‑F = 12.7 Hz), 130.0,
129.2 (d, JC‑F = 16.4 Hz), 127.5, 123.2, 121.9, 117.7 (d, JC‑F = 2.2 Hz),
117.1, 90.8 (d, JC‑F = 3.0 Hz), 20.1 (d, JC‑F = 4.5 Hz). HRMS (ESI)
m/z: [M + H]+ Calcd for C13H11ClFIN 361.9609; found: 361.9626.
N-(2-Chlorophenyl)-4-iodo-3,5-dimethylaniline (5L) The compound
was purified by flash column chromatography (ethyl acetate/
petroleum ether = 1:100) to give the product as colorless oil; yield:
1
49.9 mg, 70%. H NMR (400 MHz, CDCl3) δ 7.37 (dd, J = 8.0, 1.5
Hz, 1H), 7.28 (dd, J = 8.2, 1.6 Hz, 1H), 7.16 (td, J = 8.2, 7.8, 1.5 Hz,
8232
https://doi.org/10.1021/acs.joc.1c00681
J. Org. Chem. 2021, 86, 8226−8235

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Methyl 3-((4-iodophenyl)amino)benzoate (6q) The compound was
purified by flash column chromatography (ethyl acetate/petroleum
ether = 1:100) to give the product as a white solid, m.p. 80−81 °C;
(m, 2H), 5.68 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 143.9,
142.0, 138.3, 131.0, 130.4, 126.4, 120.3, 117.1, 95.0, 83.7. HRMS
(ESI) m/z: [M + H]+ Calcd for C12H10I2N 421.8903; found:
421.8916.
1
yield: 43.8 mg, 62%. H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H),
7.63 (d, J = 7.7 Hz, 1H), 7.57 (d, J = 8.7 Hz, 2H), 7.35 (t, J = 7.8 Hz,
1H), 7.25 (d, J = 7.9 Hz, 1H), 6.87 (d, J = 8.7 Hz, 2H), 5.82 (s, 1H),
3.92 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 167.1, 142.8,
142.5, 138.4, 131.6, 129.6, 122.7, 122.3, 120.0, 118.9, 83.3, 52.3.
HRMS (ESI) m/z: [M + H]+ Calcd for C14H13INO2 353.9991;
found: 353.9997.
N-(4-Iodophenyl)-3-isopropylaniline (6y) The compound was
purified by flash column chromatography (ethyl acetate/petroleum
ether = 1:100) to give the product as colorless oil; yield: 41. 8 mg,
62%. 1H NMR (400 MHz, CDCl3) δ 7.60−7.51 (m, 2H), 7.26 (t, J =
7.8 Hz, 1H), 6.98 (t, J = 2.0 Hz, 1H), 6.97−6.90 (m, 2H), 6.88−6.83
(m, 2H), 5.70 (s, 1H), 2.92 (m, 1H), 1.32 (s, 3H), 1.30 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 150.5, 143.4, 142.1, 138.1,
129.4, 120.2, 119.2, 117.0, 116.1, 81.9, 34.2, 24.1. HRMS (ESI) m/z:
[M + H]+ Calcd for C15H17IN 338.0406; found: 338.0406.
3-Chloro-N-(4-iodophenyl)-4-methylaniline (6z) The compound was
purified by flash column chromatography (ethyl acetate/petroleum
ether = 1:100) to give the product as a white solid, m.p. 95−96 °C;
1-(3-((4-Iodophenyl)amino)phenyl)ethan-1-one (6r) The compound
was purified by flash column chromatography (ethyl acetate/
petroleum ether = 1:100) to give the product as a white solid, m.p.
1
122−123 °C; yield: 26.9 mg, 40%. H NMR (400 MHz, CDCl3) δ
7.64 (t, J = 2.0 Hz, 1H), 7.60−7.56 (m, 2H), 7.53−7.52 (m, 1H),
7.38 (t, J = 7.8 Hz, 1H), 7.28−7.25 (m, 1H), 6.90−6.85 (m, 2H),
5.85 (s, 1H), 2.60 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
198.1, 143.1, 142.4, 138.6, 138.4, 129.8, 122.4, 121.7, 120.1, 117.2,
83.4, 26.9. HRMS (ESI) m/z: [M + H]+ Calcd for C14H13INO
338.0042; found: 338.0043.
1
yield: 38.4 mg, 56%. H NMR (400 MHz, CDCl3) δ 7.55−7.48 (m,
2H), 7.12 (d, J = 8.2 Hz, 1H), 7.07 (d, J = 2.4 Hz, 1H), 6.86 (dd, J =
8.2, 2.4 Hz, 1H), 6.81−6.76 (m, 2H), 5.59 (s, 1H), 2.33 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 142.9, 141.3, 138.3, 135.0,
131.6, 129.2, 119.4, 119.1, 117.2, 82.6, 19.4. HRMS (ESI) m/z: [M +
H]+ Calcd for C13H12ClIN 343.9703; found: 343.9687.
N-(4-Iodophenyl)-3-(trifluoromethyl)aniline (6s) The compound
was purified by flash column chromatography (ethyl acetate/
petroleum ether = 1:100) to give the product as colorless oil; yield:
5-Bromo-N-(4-iodophenyl)-2-methylaniline (6aa) The compound
was purified by flash column chromatography (ethyl acetate/
petroleum ether = 1:100) to give the product as a white solid, m.p.
1
40.6 mg, 56%. H NMR (400 MHz, CDCl3) δ 7.62−7.56 (m, 2H),
7.38 (t, J = 7.9 Hz, 1H), 7.27 (d, J = 2.1 Hz, 1H), 7.23−7.18 (m, 2H),
6.90−6.84 (m, 2H), 5.81 (s, 1H). 19F NMR (376 MHz, CDCl3) δ
−62.68. 13C{1H} NMR (100 MHz, CDCl3) δ 143.2, 141.87, 138.2,
131.9 (q, JC‑F = 32.2 Hz), 130.1, 124.1 (q, JC‑F = 270.8 Hz), 120.5 (d,
JC‑F = 1.4 Hz), 120.4, 117.8 (q, JC‑F = 3.9 Hz), 114.0 (q, JC‑F = 3.9
Hz), 84.0. HRMS (ESI) m/z: [M + H]+ Calcd for C13H10F3IN
363.9810; found: 363.9829.
1
82−83 °C; yield: 48.0 mg, 62%. H NMR (400 MHz, CDCl3) δ
7.58−7.52 (m, 2H), 7.30 (s, 1H), 7.05 (d, J = 1.2 Hz, 2H), 6.77−6.72
(m, 2H), 5.35 (s, 1H), 2.18 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 142.8, 142.2, 138.4, 132.4, 127.0, 125.1, 121.1, 120.2, 120.1,
83.2, 17.6. HRMS (ESI) m/z: [M + H]+ Calcd for C13H12BrIN
387.9198; found: 387.9209.
4-Chloro-N-(4-iodophenyl)aniline (6t) The compound was purified
by flash column chromatography (ethyl acetate/petroleum ether =
1:100) to give the product as a white solid, m.p. 75−76 °C; yield: 46.0
mg, 70%. 1H NMR (400 MHz, CDCl3) δ 7.56−7.49 (m, 2H), 7.25−
7.20 (m, 2H), 7.02−6.93 (m, 2H), 6.82−6.77 (m, 2H), 5.65 (s, 1H).
13C{1H} NMR (100 MHz, CDCl3) δ 142.8, 141.0, 138.3, 129.5,
126.5, 119.7, 119.7, 82.9. HRMS (ESI) m/z: [M + H]+ Calcd for
C12H10ClIN 329.9546; found: 329.9554.
4-Bromo-N-(4-iodophenyl)aniline (6u) The compound was purified
by flash column chromatography (ethyl acetate/petroleum ether =
1:100) to give the product as a white solid, m.p. 98−99 °C; yield: 55.9
mg, 75%. 1H NMR (400 MHz, CDCl3) δ 7.56−7.51 (m, 2H), 7.39−
7.33 (m, 2H), 6.95−6.90 (m, 2H), 6.83−6.78 (m, 2H), 5.65 (s, 1H).
13C{1H} NMR (100 MHz, CDCl3) δ 142.5, 141.6, 138.3, 132.4,
119.8, 119.8, 113.7, 83.1. HRMS (ESI) m/z: [M + H]+ Calcd for
C12H10BrIN 373.9041; found: 373.9050.
3,4-Difluoro-N-(4-iodophenyl)aniline (6ab) The compound was
purified by flash column chromatography (ethyl acetate/petroleum
ether = 1:100) to give the product as a white solid, m.p. 85−86 °C;
1
yield: 48.3 mg, 73%. H NMR (400 MHz, CDCl3) δ 7.56−7.51 (m,
2H),7.09−7.03 m, 1H), 690−6.85 (m, 1H), 6.80−6.76 (m, 2H),
6.75−6.71 (m, 1H), 5.62 (s, 1H). 19F NMR (376 MHz, CDCl3) δ
−135.68 − −135.83 (m), −146.16 − −146.27 (m). 13C{1H} NMR
(100 MHz, CDCl3) δ 151.9 (d, JC‑F = 13.4 Hz), 149.5 (d, JC‑F = 13.5
Hz), 146.8 (d, JC‑F = 12.9 Hz), 144.4 (d, JC‑F = 12.8 Hz), 142.7139.2
(dd, JC‑F = 8.2, 2.7 Hz), 138.3, 119.6, 117.8 (dd, JC‑F = 18.1, 1.7 Hz),
114.4 (dd, JC‑F = 5.7, 3.3 Hz), 107.7 (d, JC‑F = 19.9 Hz), 83.1. HRMS
(ESI) m/z: [M + H]+ Calcd for C12H9F2IN 331.9748; found:
331.9758.
2-Chloro-N-phenylaniline (7a) The compound was purified by flash
column chromatography (ethyl acetate/petroleum ether = 1:100) to
1
give the product as colorless oil; yield: 34.9 mg, 86%. H NMR (400
MHz, CDCl3) δ 7.40−7.27 (m, 4H), 7.21−7.11 (m, 3H), 7.06 (tt, J =
7.3, 1.2 Hz, 1H), 6.85−6.80 (m, 1H), 6.13 (s, 1H). 13C{1H} NMR
(100 MHz, CDCl3) δ 141.5, 140.3, 129.8, 129.5, 127.5, 122.7, 121.5,
120.4, 120.2, 115.6. HRMS (ESI) m/z: [M + H]+ Calcd for
C12H11ClN 204.0580; found: 204.0592.
Ethyl (E)-3-(4-((2-chlorophenyl)amino)phenyl)acrylate (7b) The
compound was purified by flash column chromatography (ethyl
acetate/petroleum ether = 1:100) to give the product as colorless oil;
yield: 45.7 mg, 76%. 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 15.9
Hz, 1H), 7.48−7.41 (m, 2H), 7.40−7.36 (m, 2H), 7.20−7.16 (m,
1H), 7.11−7.07 (m, 2H), 6.92−6.8 (m, 1H), 6.32 (d, J = 15.9 Hz,
1H), 6.26 (s, 1H), 4.26 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 167.4, 144.2, 144.0, 138.6,
130.0, 129.6, 127.8, 127.5, 123.2, 122.0, 118.0, 117.8, 115.5, 60.4,
14.4. HRMS (ESI) m/z: [M + H]+ Calcd for C17H17ClNO2 302.0948;
found: 302.0938.
Ethyl 4-((4-iodophenyl)amino)benzoate (6v) The compound was
purified by flash column chromatography (ethyl acetate/petroleum
ether = 1:100) to give the product as a white solid, m.p. 157−158 °C;
1
yield: 33.7 mg, 46%. H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.8
Hz, 2H), 7.58 (d, J = 8.7 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 6.92 (d, J
= 8.7 Hz, 2H), 6.17 (s, 1H), 4.34 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1
Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.6, 147.2, 141.0,
138.4, 131.5, 122.2, 121.8, 115.3, 85.0, 60.7, 14.5. HRMS (ESI) m/z:
[M + H]+ Calcd for C15H15INO2 368.0147; found: 368.0144.
2-Iodo-N-(4-iodophenyl)aniline (6w) The compound was purified
by flash column chromatography (ethyl acetate/petroleum ether =
1:100) to give the product as a white solid, m.p. 100−101 °C; yield:
1
47.1 mg, 56%. H NMR (400 MHz, CDCl3) δ 7.78 (dd, J = 7.9, 1.4
Hz, 1H), 7.60−7.54 (m, 2H), 7.25−7.17 (m, 2H), 6.91−6.84 (m,
2H), 6.69−6.65 (m, 1H), 5.85 (s, 1H). 13C{1H} NMR (100 MHz,
CDCl3) δ 143.2, 142.2, 139.8, 138.4, 129.3, 123.0, 121.3, 116.9, 89.9,
84.3. HRMS (ESI) m/z: [M + H]+ Calcd for C12H10I2N 421.8903;
found: 421.8916.
2-Chloro-N-(4-(phenylethynyl)phenyl)aniline (7c) The compound
was purified by flash column chromatography (ethyl acetate/
petroleum ether = 1:100) to give the product as colorless oil; yield:
3-Iodo-N-(4-iodophenyl)aniline (6x) The compound was purified by
flash column chromatography (ethyl acetate/petroleum ether =
1:100) to give the product as a white solid, m.p. 96−97 °C; yield:
1
54.5 mg, 90%. H NMR (400 MHz, CDCl3) δ 7.57−7.52 (m, 2H),
7.51−7.46 (m, 2H), 7.42−7.30 (m, 5H), 7.23−7.14 (m, 1H), 7.14−
7.08 (m, 2H), 6.88 (td, J = 7.7, 1.5 Hz, 1H). 13C{1H} NMR (100
MHz, CDCl3) δ 141.9, 139.1, 132.9, 131.5, 130.0, 128.4, 128.0, 127.5,
1
35.3 mg, 42%. H NMR (400 MHz, CDCl3) δ 7.61−7.53 (m, 2H),
7.40 (s, 1H), 7.30−7.28 (m, 1H), 7.00 (d, J = 4.0 Hz, 2H), 6.89−6.81
8233
https://doi.org/10.1021/acs.joc.1c00681
J. Org. Chem. 2021, 86, 8226−8235

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
123.6, 122.6, 121.5, 118.5, 116.9, 116.4, 89.6, 88.6. HRMS (ESI) m/z:
[M + H]+ Calcd for C20H15ClN 304.0893; found: 304.0885.
N-(2-Chlorophenyl)-[1,1′-biphenyl]-4-amine (7d) The compound
was purified by flash column chromatography (ethyl acetate/
petroleum ether = 1:100) to give the product as a white solid, m.p.
67−68 °C; yield: 43.5 mg, 78%. 1H NMR (400 MHz, CDCl3) δ 7.53
(d, J = 7.3 Hz, 2H), 7.49 (d, J = 8.5 Hz, 2H), 7.37 (t, J = 7.6 Hz, 2H),
7.32 (dd, J = 8.0, 1.5 Hz, 1H), 7.30−7.23 (m, 2H), 7.13 (d, J = 8.4
Hz, 2H), 7.11−7.04 (m, 1H), 6.76 (td, J = 7.7, 1.5 Hz, 1H), 6.10 (s,
1H). 13C{1H} NMR (100 MHz, CDCl3) δ 141.0, 140.7, 140.1, 135.4,
129.9, 128.9, 128.1, 127.6, 126.9, 126.7, 121.8, 120.7, 120.2, 116.0.
HRMS (ESI) m/z: [M + H]+ Calcd for C18H15ClN 280.0893; found:
280.0891.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00681
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Natural Science Foundation
of China (no. 21772139), the Major Basic Research Project of
the Natural Science Foundation of Jiangsu Higher Education
Institutions (17KJA150006), the Jiangsu Province Natural
Science Found for Distinguished Young Scholars
(BK20180041), Project of Scientific and Technologic Infra-
structure of Suzhou (SZS201708), and the PAPD Project. The
project was also supported by the Open Research Fund of the
School of Chemistry and Chemical Engineering, Henan
Normal University.
4-((2-Chlorophenyl)amino)phenol (7e) The compound was purified
by flash column chromatography (ethyl acetate/petroleum ether =
1
1:5) to give the product as colorless oil; yield: 22.3 mg, 51%. H
NMR (400 MHz, CDCl3) δ 7.33 (dd, J = 7.9, 1.5 Hz, 1H), 7.11−7.05
(m, 3H), 6.97 (dd, J = 8.2, 1.5 Hz, 1H), 6.87−6.81 (m, 2H), 6.73 (td,
J = 7.6, 1.5 Hz, 1H), 5.95 (s, 1H), 5.10 (s, 1H). 13C{1H} NMR (100
MHz, CDCl3) δ 152.2, 142.2, 134.3, 129.6, 127.6, 124.9, 120.1, 119.2,
116.4, 114.0. HRMS (ESI) m/z: [M + H]+ Calcd for C12H11ClNO
220.0529; found: 220.0531.
REFERENCES
■
(1) (a) Valgimigli, L.; Pratt, D. A. Maximizing the Reactivity of
Phenolic and Aminic Radical-Trapping Antioxidants: Just Add
Nitrogen! Acc. Chem. Res. 2015, 48, 966−975. (b) Kurti, L.
Streamlining Amine Synthesis. Science 2015, 348, 863−864.
(c) Chu, J. C. K.; Dalton, D. M.; Rovis, T. Zn-Catalyzed Enantio-
and Diastereoselective Formal [4 + 2] Cycloaddition Involving Two
Electron-Deficient Partners: Asymmetric Synthesis of Piperidines
from 1-Azadienes and Nitro-Alkenes. J. Am. Chem. Soc. 2015, 137,
4445−4452. (d) O’Reilly, M. E.; Veige, A. S. Trianionic Pincer and
Pincer-Type Metal Complexes and Catalysts. Chem. Soc. Rev. 2014,
43, 6325−6369.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00681.
1H, 13C, and 19F NMR spectra for all compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
(2) (a) Kunz, K.; Scholz, U.; Ganzer, D. Renaissance of Ullmann and
Goldberg Reactions - Progress in Copper Catalyzed C-N-, C-O- and
C-S-Coupling. Synlett 2003, 2428−2439. (b) Evano, G.; Blanchard,
N.; Toumi, M. Copper-Mediated Coupling Reactions and Their
Applications in Natural Products and Designed Biomolecules
Synthesis. Chem. Rev. 2008, 108, 3054−3131. (c) Ley, S. V.;
Thomas, A. W. Modern Synthetic Methods for Copper-Mediated
C(aryl)-O, C(aryl)-N, and C(aryl)-S Bond Formation. Angew. Chem.,
Int. Ed. 2003, 42, 5400−5449.
(3) (a) Lam, P. Y. S.; Bonne, D.; Vincent, G.; Clark, C. G.; Combs,
A. P. N-Arylation of α-Aminoesters with P-Tolylboronic Acid
Promoted by copper(II) Acetate. Tetrahedron Lett. 2003, 44, 1691−
1694. (b) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P.
New N- and O-Arylations with Phenylboronic Acids and Cupric
Acetate. Tetrahedron Lett. 1998, 39, 2933−2936. (c) Lam, P. Y. S.;
Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav, P. K. Copper-Catalyzed
General C-N and C-O Bond Cross-Coupling with Arylboronic Acid.
Tetrahedron Lett. 2001, 42, 3415−3418. (d) Antilla, J. C.; Buchwald,
S. L. Copper-Catalyzed Coupling of Arylboronic Acids and Amines.
Org. Lett. 2001, 3, 2077−2079. (e) Lam, P. Y. S.; Clark, C. G.;
Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A.
New Aryl/heteroaryl C-N Bond Cross-Coupling Reactions via
Arylboronic Acid/cupric Acetate Arylation. Tetrahedron Lett. 1998,
39, 2941−2944.
Zhibin Huang − Key Laboratory of Organic Synthesis of
Jiangsu Province, College of Chemistry, Chemical Engineering
and Materials Science, Soochow University, Suzhou 215123,
P. R. China; Email: zbhuang@suda.edu.cn
Da-Qing Shi − Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and
Materials Science, Soochow University, Suzhou 215123, P. R.
China; orcid.org/0000-0003-2262-8491; Email: sqshi@
suda.edu.cn
Yingsheng Zhao − Key Laboratory of Organic Synthesis of
Jiangsu Province, College of Chemistry, Chemical Engineering
and Materials Science, Soochow University, Suzhou 215123,
P. R. China; School of Chemistry and Chemical Engineering,
Henan Normal University, Henan 453007, China;
orcid.org/0000-0002-6142-7839; Email: yszhao@
suda.edu.cn
Authors
Yujie Chen − Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and
Materials Science, Soochow University, Suzhou 215123, P. R.
China
Yaqiqi Jiang − Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and
Materials Science, Soochow University, Suzhou 215123, P. R.
China
Sai Shu − Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and
Materials Science, Soochow University, Suzhou 215123, P. R.
China
Shan Yang − Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and
Materials Science, Soochow University, Suzhou 215123, P. R.
China
(4) (a) Louie, J.; Hartwig, J. F. Palladium-Catalyzed Synthesis of
Arylamines from Aryl Halides. Mechanistic Studies Lead to Coupling
in the Absence of Tin Reagents. Tetrahedron Lett. 1995, 36, 3609−
3612. (b) Surry, D. S.; Buchwald, S. L. Dialkylbiaryl Phosphines in
Pd-Catalyzed Amination: A User’s Guide. Chem. Sci. 2011, 2, 27−50.
(c) Inoue, F.; Kashihara, M.; Yadav, M. R.; Nakao, Y. Buchwald-
Hartwig Amination of Nitroarenes. Angew. Chem., Int. Ed. 2017, 56,
13307−13309. (d) Dorel, R.; Grugel, C. P.; Haydl, A. M. The
Buchwald−Hartwig Amination After 25 Years. Angew. Chem., Int. Ed.
2019, 58, 17118−17129.
(5) (a) Collman, J. P.; Zhong, M. An Efficient Diamine·Copper
Complex-Catalyzed Coupling of Arylboronic Acids with Imidazoles.
Org. Lett. 2000, 2, 1233−1236. (b) Klapars, A.; Antilla, J. C.; Huang,
8234
https://doi.org/10.1021/acs.joc.1c00681
J. Org. Chem. 2021, 86, 8226−8235

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
X.; Buchwald, S. L. A General and Efficient Copper Catalyst for the
Amidation of Aryl Halides and the N-Arylation of Nitrogen
Heterocycles. J. Am. Chem. Soc. 2001, 123, 7727−7729. (c) Quach,
T. D.; Batey, R. A. Ligand- and Base-Free Copper(II)-Catalyzed C−N
Bond Formation: Cross-Coupling Reactions of Organoboron
Compounds with Aliphatic Amines and Anilines. Org. Lett. 2003, 5,
4397−4400. (d) Ruiz-Castillo, P.; Blackmond, D. G.; Buchwald, S. L.
Rational Ligand Design for the Arylation of Hindered Primary Amines
Guided by Reaction Progress Kinetic Analysis. J. Am. Chem. Soc. 2015,
137, 3085−3092.
(14) Zhao, Y.; Yan, H.; Lu, H.; Huang, Z.; Lei, A. Para-Selective C−
H Bond Functionalization of Iodobenzenes. Chem. Commun. 2016,
52, 11366−11369.
(15) Kwon, Y.-D.; Son, J.; Chun, J.-H. Catalyst-Free Aromatic
Radiofluorination via Oxidized Iodoarene Precursors. Org. Lett. 2018,
20, 7902−7906.
(16) Tian, J.; Luo, F.; Zhang, Q.; Liang, Y.; Li, D.; Zhan, Y.; Kong,
L.; Wang, Z.-X.; Peng, B. Asymmetric Iodonio-[3,3]-Sigmatropic
Rearrangement to Access Chiral α-Aryl Carbonyl Compounds. J. Am.
Chem. Soc. 2020, 142, 6884−6890.
(17) Wu, Y.; Izquierdo, S.; Vidossich, P.; Lledós, A.; Shafir, A. NH-
Heterocyclic Aryliodonium Salts and Their Selective Conversion into
N 1-Aryl-5-Iodoimidazoles. Angew. Chem., Int. Ed. 2016, 55, 7152−
7156.
(18) Zhao, D.; Wu, N.; Zhang, S.; Xi, P.; Su, X.; Lan, J.; You, J.
Synthesis of Phenol, Aromatic Ether, and Benzofuran Derivatives by
Copper-Catalyzed Hydroxylation of Aryl Halides. Angew. Chem., Int.
Ed. 2009, 48, 8729−8732.
(19) Narisada, M.; Horibe, I.; Watanabe, F.; Takeda, K. Selective
Reduction of Aryl Halides and α,β-Unsaturated Esters with Sodium
Borohydride-Cuprous Chloride in Methanol and Its Application to
Deuterium Labeling. J. Org. Chem. 1989, 54, 5308−5313.
(20) A relevant finding was reported by Li et al. during the course of
our submission. Yang, P.; Wang, X.; Wang, L.; He, J.; Zhang, Q.; Li,
D. Oxidative cross-dehydrogenative coupling between iodoarenes and
acylanilides for C-N bond formation under metal-free conditions. Org.
Chem. Front. 2021, 8, 2556−2562.
(6) (a) He, C.; Chen, C.; Cheng, J.; Liu, C.; Liu, W.; Li, Q.; Lei, A.
Aryl Halide Tolerated Electrophilic Amination of Arylboronic Acids
with N-Chloroamides Catalyzed by CuCl at Room Temperature.
Angew. Chem., Int. Ed. 2008, 47, 6414−6417. (b) Yoo, W.-J.;
Tsukamoto, T.; Kobayashi, S. Visible-Light-Mediated Chan-Lam
Coupling Reactions of Aryl Boronic Acids and Aniline Derivatives.
Angew. Chem., Int. Ed. 2015, 54, 6587−6590. (c) Oderinde, M. S.;
Jones, N. H.; Juneau, A.; Frenette, M.; Aquila, B.; Tentarelli, S.;
Robbins, D. W.; Johannes, J. W. Highly Chemoselective Iridium
Photoredox and Nickel Catalysis for the Cross-Coupling of Primary
Aryl Amines with Aryl Halides. Angew. Chem., Int. Ed. 2016, 55,
13219−13223. (d) Liu, R. Y.; Dennis, J. M.; Buchwald, S. L. The
Quest for the Ideal Base: Rational Design of a Nickel Precatalyst
Enables Mild, Homogeneous C−N Cross-Coupling. J. Am. Chem. Soc.
2020, 142, 4500−4507. (e) Bismuto, A.; Delcaillau, T.; Muller, P.;
̈
Morandi, B. Nickel-Catalyzed Amination of Aryl Thioethers: A
Combined Synthetic and Mechanistic Study. ACS Catal. 2020, 10,
4630−4639. (f) Dhital, R. N.; Sen, A.; Sato, T.; Hu, H.; Ishii, R.;
Hashizume, D.; Takaya, H.; Uozumi, Y.; Yamada, Y. M. A. Activator-
Promoted Aryl Halide-Dependent Chemoselective Buchwald−
Hartwig and Suzuki−Miyaura Type Cross-Coupling Reactions. Org.
Lett. 2020, 22, 4797−4801.
(21) Cardenal, A. D.; Maity, A.; Gao, W.-Y.; Ashirov, R.; Hyun, S.-
M.; Powers, D. C. Iodosylbenzene Coordination Chemistry Relevant
to Metal−Organic Framework Catalysis. Inorg. Chem. 2019, 58,
10543−10553.
(22) (a) Zhou, M.; Hintermair, U.; Hashiguchi, B. G.; Parent, A. R.;
Hashmi, S. M.; Elimelech, M.; Periana, R. A.; Brudvig, G. W.;
Crabtree, R. H. Cp* Iridium Precatalysts for Selective C-H Oxidation
with Sodium Periodate as the Terminal Oxidant. Organometallics
2013, 32, 957−965. (b) Koleda, O.; Broese, T.; Noetzel, J.; Roemelt,
M.; Suna, E.; Francke, R. Synthesis of Benzoxazoles Using
Electrochemically Generated Hypervalent Iodine. J. Org. Chem.
2017, 82, 11669−11681. (c) Wu, L.; Song, Y.; Li, Z.; Guo, J.; Yao,
X. Copper(II)-Catalysed Aerobic Oxidative Coupling of Arylamines
with Hexafluoroisopropanol: An Alternative Methodology for
Constructing Fluorinated Compounds. Adv. Synth. Catal. 2021, 363,
268−274.
(7) (a) Itoh, N.; Sakamoto, T.; Miyazawa, E.; Kikugawa, Y.
Introduction of a Hydroxy Group at the Para Position and N
-Iodophenylation of N -Arylamides Using Phenyliodine(III) Bis-
(Trifluoroacetate). J. Org. Chem. 2002, 67, 7424−7428. (b) Li, J.;
Zheng, X.; Li, W.; Zhou, W.; Zhu, W.; Zhang, Y. Transition-Metal
Free N-Arylation of Cyanamides by Diaryliodonium Triflates in
Aqueous Media. New J. Chem. 2016, 40, 77−80. (c) Li, G.; Nykaza, T.
V.; Cooper, J. C.; Ramirez, A.; Luzung, M. R.; Radosevich, A. T. An
III
V
Improved P
/P O-Catalyzed Reductive C−N Coupling of
Nitroaromatics and Boronic Acids by Mechanistic Differentiation of
Rate- and Product-Determining Steps. J. Am. Chem. Soc. 2020, 142,
6786−6799.
(23) Shi, Y.; Liu, J.; Yang, Y.; You, J. General Rhodium-Catalyzed
Oxidative Cross-Coupling Reactions between Anilines: Synthesis of
Unsymmetrical 2,2′-Diaminobiaryls. Chem. Commun. 2019, 55,
5475−5478.
(8) Roscales, S.; Csáky, A. G. Synthesis of Di(hetero)arylamines
̈
from Nitrosoarenes and Boronic Acids: A General, Mild, and
Transition-Metal-Free Coupling. Org. Lett. 2018, 20, 1667−1671.
(9) Tinnis, F.; Stridfeldt, E.; Lundberg, H.; Adolfsson, H.; Olofsson,
B. Metal-Free N-Arylation of Secondary Amides at Room Temper-
ature. Org. Lett. 2015, 17, 2688−2691.
(10) Barros, M. T.; Dey, S. S.; Maycock, C. D.; Rodrigues, P. Metal-
Free Direct Amination/aromatization of 2-Cyclohexenones to Iodo-
N-Arylanilines and N-Arylanilines Promoted by Iodine. Chem.
Commun. 2012, 48, 10901−10903.
(11) Mowdawalla, C.; Ahmed, F.; Li, T.; Pham, K.; Dave, L.; Kim,
G.; Dempsey Hyatt, I. F. Hypervalent Iodine-Guided Electrophilic
Substitution: Para-Selective Substitution across Aryl Iodonium
Compounds with Benzyl Groups. Beilstein J. Org. Chem. 2018, 14,
1039−1045.
(12) Wu, Y.; Bouvet, S.; Izquierdo, S.; Shafir, A. Synthesis of
Polysubstituted Iodoarenes Enabled by Iterative Iodine-Directed Para
and Ortho C-H Functionalization. Angew. Chem., Int. Ed. 2019, 58,
2617−2621.
(13) Noorollah, J.; Im, H.; Siddiqi, F.; Singh, N.; Spatola, N. R.;
Chaudhry, A.; Jones, T. J.; Hyatt, I. F. D. Para-Selective Benzylation
of Aryl Iodides by the in Situ Preparation of ArIF2: A Hypervalent
Iodine-Guided Electrophilic Substitution. Eur. J. Org. Chem. 2020,
2020, 2302−2305.
8235
https://doi.org/10.1021/acs.joc.1c00681
J. Org. Chem. 2021, 86, 8226−8235