Copper-Mediated monochlorination of anilines and nitrogen-containing heterocycles

Article abstract of DOI:10.1080/00397911.2018.1518531

A simple and selective copper(II) chloride-mediated monochlorination of anilines and nitrogen-containing heterocycles has been developed. Stirring a mixture of aniline, copper(II) chloride, lithium chloride in EtOH under reflux condition produced 4-chloroaniline with high yield. Eighteen substrates including substituted anilines, N-substituted anilines, N,N-disubstituted anilines, 5-nitroindole and carbazole were all reactive and afforded desired products in moderate to excellent yields (52%–98%).

Full text of DOI:10.1080/00397911.2018.1518531

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Copper-Mediated monochlorination of anilines
and nitrogen-containing heterocycles
Xue-Yan Yang, Hong-Yi Zhao, Shuai Mao & San-Qi Zhang
To cite this article: Xue-Yan Yang, Hong-Yi Zhao, Shuai Mao & San-Qi Zhang (2018):
Copper-Mediated monochlorination of anilines and nitrogen-containing heterocycles, Synthetic
Communications, DOI: 10.1080/00397911.2018.1518531
To link to this article: https://doi.org/10.1080/00397911.2018.1518531
View supplementary material
Published online: 08 Oct 2018.
Submit your article to this journal
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=lsyc20

R
SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2018.1518531
Copper-Mediated monochlorination of anilines and
nitrogen-containing heterocycles
Xue-Yan Yang, Hong-Yi Zhao, Shuai Mao, and San-Qi Zhang
Department of Medicinal Chemistry, School of Pharmacy, Xi’an Jiaotong University, Xi’an, P. R. China
ABSTRACT
ARTICLE HISTORY
Received 16 July 2018
A simple and selective copper(II) chloride-mediated monochlorina-
tion of anilines and nitrogen-containing heterocycles has been devel-
oped. Stirring a mixture of aniline, copper(II) chloride, lithium
chloride in EtOH under reflux condition produced 4-chloroaniline
with high yield. Eighteen substrates including substituted anilines,
N-substituted anilines, N,N-disubstituted anilines, 5-nitroindole and
carbazole were all reactive and afforded desired products in moder-
ate to excellent yields (52%–98%).
KEYWORDS
Aniline; chlorination;
copper chloride;
lithium chloride
GRAPHICAL ABSTRACT
Introduction
Aryl chlorides are found in a wide variety of natural products[1,2] and are widely used
as building blocks for drugs,[3] pesticides,[4] and other valuable compounds. As a special
class of aryl chlorides, chlorinated aryl amines are involved in many organic reactions,[5]
especially coupling[6–8] and substitution reactions. Therefore, much attention has been
paid to the synthesis of chlorinated aryl amines. Traditionally, aromatic chlorides are
obtained through electrophilic aromatic substitution (EAS)[9] using Cl2 or NCS[10,11] as
a chlorine source and by Sandmeyer reaction of anilines.[12] However, due to the harsh
conditions and long reaction time of these methods, a series of new methods have been
developed for the chlorination. In 2010, Saikia put forward a novel way to chlorinate
aniline in the presence of HCl/H2O2 using a mixture of CH3CN and H2O as solvent,
but the use of expensive catalyst and nanoparticle group limited its application.[13] Then
CONTACT San-Qi Zhang
sqzhang@xjtu.edu.cn
Department of Medicinal Chemistry, School of Pharmacy, Xi’an
Jiaotong University, Xi’an, Shaanxi 710061, P. R. China.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2018 Taylor & Francis Group, LLC

2
X.-Y. YANG ET AL.
(a) Copper-catalyzed chlorination of anilines with HOAc and O2
(b) This work:Copper-mediated chlorination of anilinesand
nitrogen-containing heterocycles in EtOH
Scheme 1. (a) Copper-catalyzed chlorination of anilines with HOAc and O2. (b) Copper-mediated
chlorination of anilines and nitrogen-containing heterocycles in EtOH.
attention was paid to transition-metal-catalyzed reactions, especially the transition-
metal-catalyzed chelation-directed aryl C–H activation.[14] For example, nickel-catalyzed
ortho-chlorination of aryl C–H bonds using a removable auxiliary was reported in
2016.[15] In the same year, Rh(III)-catalyzed ortho-chlorination of benzene derivatives
was demonstrated by Lied.[16] In 2017, Sutherland brought up a new way for ortho-
chlorination of activated arenes using iron(III) catalyst.[17] However, all of these
reported reactions required the pre-installation of directing group, which reduced the
scope of substrates. A metal-free protocol for chlorination of a range of 8-substituted
quinoline derivatives using trichloroisocyanuric acid (TCCA) as efficient chlorine source
was established by Motati.[18]
In 2008, Gusevskaya reported copper-catalyzed chlorination of aniline derivatives.
However, environment-unfriendly acetic acid was used as solvent under oxygen atmos-
phere in the reaction (Scheme 1a). In addition, N-substituted aniline exhibited very low
reactivity under the reported reaction conditions.[19] Hence, it is necessary to develop a
more environment-friendly and operationally simple method for the synthesis of chlori-
nated aniline derivatives or analogs with a broader range of substrates.
In this article, we describe the synthesis of chlorinated aniline derivatives and nitro-
gen-containing heterocycles employing cheap and readily available copper(II) chloride
as a chlorinated reagent in EtOH without additional need of an oxidant (Scheme 1b). A
wide range of substrates can be site-selectively and efficiently monochlorinated under
optimized conditions. In general, the advantages of this method include the use of
EtOH as solvent, simple operation, a wide range of substrates and high selectivity.
Results and discussion
Optimization of reaction conditions
Initially, the reaction of 1a with CuCl2ꢀ2H2O (120 mol%) was investigated in the presence
of Bu4NCl in THF at 60ꢁC for 10h, and only trace amount of 4-chloroaniline (1b) was
detected (Table 1, entry 1). Then a solvent screen was performed using dioxane, CH3CN,

R
SYNTHETIC COMMUNICATIONSV
3
Table 1. Optimization of reaction conditions for chlorinationa.
Entry
Cu salt (mol %)
Additive
Solvent
T (ꢁC)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
CuCl2ꢀ2H2O (120)
CuCl2ꢀ2H2O (120)
CuCl2ꢀ2H2O (120)
CuCl2ꢀ2H2O (120)
CuCl2ꢀ2H2O (120)
CuCl2ꢀ2H2O (120)
CuCl2ꢀ2H2O (120)
Cu(OAc)2ꢀH2O (120)
CuCl2ꢀ2H2O (120)
CuCl2ꢀ2H2O (200)
CuCl2ꢀ2H2O (300)
CuCl2ꢀ2H2O (300)
CuCl2ꢀ2H2O (300)
CuCl2ꢀ2H2O (300)
CuCl2ꢀ2H2O (300)
Bu4NCl
Bu4NCl
Bu4NCl
Bu4NCl
Bu4NCl
Bu4NCl
Bu4NCl
Bu4NCl
–
THF
60
80
80
80
80
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
16
15
15
<10
<10
<10
19
0
22
34
61
Dioxane
CH3CN
DCE
DMSO
DMF
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
80
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
9
10
11
12
13
14
15
–
–
LiClꢀH2O
LiClꢀH2O
NH4Cl
NaCl
85
83c
28
48
aReaction conditions: 1a (1 mmol), additive (1 mmol), solvent (2 mL); bIsolated yield; Under argon.
c
1,2-dichloroethane (DCE), DMSO, DMF, EtOH (Table 1, entries 2–7). The results indi-
cated that EtOH was the best solvent among those examined. When Cu(OAc)2ꢀH2O
replaced CuCl2ꢀ2H2O, no product was detected (Table 1, entry 8). To determine the opti-
mal quantity of CuCl2ꢀ2H2O necessary for chlorination, the amount of the salt was varied.
The yield improved by nearly 3-fold when the amount of CuCl2ꢀ2H2O was increased
from 120 mol% to 300 mol% (Table 1, entries 9–11). In addition, the isolated yield
increased to 85% when LiClꢀH2O was used as an additive (Table 1, entry 12). The use of
NH4Cl or NaCl as additive was, however, not beneficial (Table 1, entries 14–15).
Performing the reaction under the argon atmosphere did not impact on the yield (Table
1, entry 13). To sum up, the optimized reaction conditions were established as follows:
300 mol% of CuCl2ꢀ2H2O, 100 mol% of LiClꢀH2O, EtOH as solvent at reflux.
Scope of substrates
With the optimized conditions in hand, we turned to investigate the substrate scope of
chlorination. As shown in Table 2, substituted anilines (2a–10a), N-substituted anilines
(11a–13a), N, N-disubstituted anilines (14a–16a), and heterocycles (17a–18a) were all
reactive and generated anticipative products (2b–18b) in moderate to excellent
yields (52–98%).
The chlorination of the anilines took place at the para–position of the amino group
(2b–8b, 11b–12b, 14b–16b), while the ortho–chlorinated products formed in the case
where there was a substituent at the para–position of the amino group (9b–10b, 13b).
In addition, all anilines were reactive irrespective of the electron-withdrawing or elec-
tron-donating groups present. However, the yield of the product was higher for the ani-
lines with electron-donating groups (2b–6b) than those with electron-withdrawing
groups (8b–10b). Interestingly, 8-aminoquinoline, which was reported as a directing

4
X.-Y. YANG ET AL.
Table 2. Reaction scope of chlorinationa,b
.
aReaction conditions: substrate (2 mmol), CuCl2ꢀ2H2O (6 mmol), LiClꢀH2O (2 mmol) in EtOH (4 mL), 3–50 h;
bIsolated yields.
group for C–H activation by Dauglis,[20] gave the expectant product in 93% yield. As
expected, the secondary anilines, the nitrogen atom of which was attached to either a
chain or a cyclic substituent, produced chlorinated products in moderate to high yields
(11b–13b, 53%–87%). Furthermore, cyclic tertiary aniline and branched tertiary aniline
were chlorinated to produce chlorine-substituted products under the reaction conditions
(14b–16b, 73%–84%). To our delight, nitrogen-containing heterocycles were also active
substrates under the present reaction conditions and gave acceptable to excellent yields
of the desired products. 5-Nitroindole was selectively chlorinated to provide 3-chloro-5-
nitroindole (17b, 98%), while carbazole was chlorinated at the para-position of the
nitrogen atom to give 3-chloro-9H-carbazole (18b, 71%).
Proposed mechanism
In 2006, Yu put forward a mechanism for chlorination of 2-phenylpyridine.[21]
Subsequently, Gusevskaya showed us the mechanism of chlorination of aniline in
2008.[19] Based on the reported mechanisms, we proposed a single electron transfer
(SET) mechanism for the chlorination of aniline derivatives. As shown in Scheme 2,
intermediate c was produced from complex a through a single electron transfer process,
which was subsequently attacked by chlorine ion to give intermediate d and CuCl.

R
SYNTHETIC COMMUNICATIONSV
5
Scheme 2. Proposed mechanism for chlorination of aniline derivatives.
Intermediate d went through single electron transfer process to provide chlorinated
product b, CuCl and HCl. According to the proposed mechanism, the yield of the ani-
lines with electron-donating substituent was higher than those with electron-withdraw-
ing substituent due to the fact that the former was much easier to transfer electron
to copper(II).
Conclusions
In summary, an approach for selective monochlorination of the aniline derivatives and
nitrogen-containing heterocycles mediated by copper(II) chloride was developed.
Substituted anilines, N-substituted anilines, N,N-disubstituted anilines, 5-nitroindole,
and carbazole were all reactive. Moreover, we showed the proposed mechanism for the
chlorination. These findings provide a simple synthetic strategy to prepare chlorinated
anilines and heterocyles.
Experimental section
All the regular chemicals were purchased from commercial sources with purity over
1
95% and used without further purification. H and 13C NMR spectra were received
using a Bruker 400 MHz (400 MHz or 100 MHz, respectively) spectrometer. Chemical
shifts (d) and coupling constants (J) were reported in ppm and Hz, respectively. Mass
(MS) analysis was obtained using LC-MS1000 (Skyray Instrument) with ESI. Flash chro-
matography was performed using standard grade silica gel (200–300 mesh). Analytical
TLC was performed with GF254 precoated silica gel plates with visualization by
UV (254 nm).
General procedure for the synthesis of 1b–18b
A round-bottomed flask (25 mL) was charged with substrate (2 mmol), CuCl2ꢀ2H2O
(6 mmol), LiClꢀH2O (2 mmol) and EtOH (4 mL). The resulting reaction mixture was

6
X.-Y. YANG ET AL.
stirred at reflux. After the completion of the reaction monitored by TLC, EtOH was
removed under reduced pressure. Then ammonium hydroxide (4 mL, 25%) and water
(10 mL) were added and the aqueous phase was extracted with ethyl acetate (10 mL
ꢂ3). The combined organic phase was washed with brine (8 mL ꢂ 3) and dried over
anhydrous Na2SO4. The solvent was removed under reduced pressure. The crude
mixture was purified by chromatography on silica gel to obtain the desired products.
4 -chloroaniline (1b)[19]
1
Grey solid; yield: 215.9 mg, 85%; M.p.: 66.7–69.3 ꢁC (lit: 67–70 ꢁC); H NMR (400 MHz,
CDCl3) d 7.10 (d, J ¼ 8.7 Hz, 2H), 6.60 (d, J ¼ 8.7 Hz, 2H), 3.63 (s, 2H). 13C NMR
(100 MHz, CDCl3) d 145.0, 129.1 (2C), 123.1, 116.3 (2C). MS (ESIþ): m/z calcd for
C6H7NCl [M þ H]þ 128.0; found 127.8 (35Cl, 100%), 129.7 (37Cl, 45%). All other char-
acterization data and spectra of compounds are given in Supplementary data.
Funding
Financial support from The National Natural Science Foundation of China (Grant No. 21602169)
is gratefully acknowledged.
Reference
[1] Bohlmann, F.; Knauf, W.; Misra, L. N. Structure and Synthesis of Chlorophenol
Derivatives from Helichrysum Species. Tetrahedron. 1984, 40, 4987. DOI: 10.1016/S0040-
4020(01)91337-7.
[2] Gribble, G. W. The Diversity of Naturally Produced Organohalogens. Chemosphere. 2003,
52, 289. DOI: 10.1016/S0045-6535(03)00207-8.
[3] Lang, M.; Spiteller, P.; Hellwig, V.; Steglich, W. Stephanosporin, a “Traceless” Precursor of
2-Chloro-4-nitrophenol in the Gasteromycete Stephanospora caroticolor We thank the
Deutsche Forschungsgemeinschaft for financial support (SFB 369)). Angew. Chem. Int.
Ed. Engl. 2001, 40, 1704. DOI: 10.1002/1521-3773(20010504)40:9<1704::AID-
ANIE17040>3.0.CO;2-L.
[4] Peters, E. J.; Lowance, S. A. Weed Sci. 2017, 20, 140.
[5] Cernak, T.; Dykstra, K. D.; Tyagarajan, S.; Vachal, P.; Krska, S. W. The Medicinal
Chemist’s Toolbox for Late Stage Functionalization of Drug-like Molecules. Chem. Soc.
Rev. 2016, 45, 546. DOI: 10.1039/C5CS00628G.
[6] Tian, J.; Moeller, K. D. Electrochemically Assisted Heck reactions. Org. Lett. 2005, 7,
5381. DOI: 10.1021/ol0519487.
[7] Lin ; Liu, L.; Fu, Y.; Luo, S.-W.; Chen, Q.; Guo, Q.-X. Organometallics 2004, 23, 2114.
DOI: 10.1021/om034067h.
ꢀ
[8] Calo, V.; Nacci, A.; Monopoli, A.; Ieva, E.; Cioffi, N. Copper Bronze Catalyzed Heck
Reaction in Ionic liquids. Org. Lett. 2005, 7, 617. DOI: 10.1021/ol047593t.
[9] David, D. L. M.; Bernard, P. Electrophilic Halogenation; Cambridge University Press: New
York, 1976.
[10] Maddox, S. M.; Nalbandian, C. J.; Smith, D. E.; Gustafson, J. L. A Practical Lewis Base
Catalyzed Electrophilic Chlorination of Arenes and heterocycles. Org. Lett. 2015, 17, 1042.
DOI: 10.1021/acs.orglett.5b00186.
[11] Maddox, S. M.; Dinh, A. N.; Armenta, F.; Um, J.; Gustafson, J. L. The Catalyst-Controlled
Regiodivergent Chlorination of Phenols. Org. Lett. 2016, 18, 5476. DOI: 10.1021/
acs.orglett.6b02650.

R
SYNTHETIC COMMUNICATIONSV
7
[12] Hodgson, H. H. The Sandmeyer reaction. Chem. Rev. 1947, 40, 251. DOI: 10.1021/
cr60126a003.
[13] Saikia, L.; Rajesh, M.; Srinivas, D.; Ratnasamy, P. Regiospecific Oxyhalogenation of
Aromatics over SBA-15-Supported Nanoparticle Group IV–VI Metal Oxides. Catal. Lett.
2010, 137, 190. DOI: 10.1007/s10562-010-0350-z.
[14] Liu, X.-H.; Park, H.; Hu, J.-H.; Hu, Y.; Zhang, Q.-L.; Wang, B.-L.; Sun, B.; Yeung, K.-S.;
Zhang, F.-L.; Yu, J.-Q. Diverse ortho -C(sp 2)–H Functionalization of Benzaldehydes
Using Transient Directing Groups. J. Am. Chem. Soc. 2017, 139, 888. DOI: 10.1021/
jacs.6b11188.
[15] Zhan, B.-B.; Liu, Y.-H.; Hu, F.; Shi, B.-F. Nickel-catalyzed ortho-halogenation of unacti-
vated (hetero)aryl C-H bonds with lithium halides using a removable auxiliary. Chem.
Commun. (Camb.) 2016, 52, 4934. DOI: 10.1039/C6CC00822D.
ꢃ
[16] Lied, F.; Lerchen, A.; Knecht, T.; Mu€ck-Lichtenfeld, C.; Glorius, F. Versatile Cp Rh(III)-
Catalyzed Selective Ortho -Chlorination of Arenes and Heteroarenes. ACS Catal. 2016, 6,
7839. DOI: 10.1021/acscatal.6b02227.
[17] Mostafa, M. A. B.; Bowley, R. M.; Racys, D. T.; Henry, M. C.; Sutherland, A. Iron(III)-
Catalyzed Chlorination of Activated Arenes. J. Org. Chem. 2017, 82, 7529. DOI: 10.1021/
acs.joc.7b01225.
[18] Motati, D. R.; Uredi, D.; Watkins, E. B. A General Method for the metal-free, regioselec-
tive, remote C-H halogenation of 8-substituted quinolines. Chem. Sci. 2018, 9, 1782.
DOI: 10.1039/C7SC04107A.
[19] Menini, L.; da Cruz Santos, J. C.; Gusevskaya, E. V. Copper-Catalyzed Oxybromination
and Oxychlorination of Primary Aromatic Amines Using LiBr or LiCl and Molecular
Oxygen. Adv. Synth. Catal. 2008, 350, 2052. DOI: 10.1002/adsc.200800223.
[20] Truong, T.; Klimovica, K.; Daugulis, O. Copper-catalyzed, directing group-assisted fluorin-
ation of arene and heteroarene C-H bonds. J. Am. Chem. Soc. 2013, 135, 9342. DOI:
10.1021/ja4047125.
[21] Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. Cu(II)-catalyzed functionalizations of aryl
C-H bonds using O2 as an oxidant. J. Am. Chem. Soc. 2006, 128, 6790. DOI: 10.1021/
ja061715q.