Iron(III)-Catalyzed Chlorination of Activated Arenes

Article abstract of DOI:10.1021/acs.joc.7b01225

A general and regioselective method for the chlorination of activated arenes has been developed. The transformation uses iron(III) triflimide as a powerful Lewis acid for the activation of N-chlorosuccinimide and the subsequent chlorination of a wide range of anisole, aniline, acetanilide, and phenol derivatives. The reaction was utilized for the late-stage mono- and dichlorination of a range of target compounds such as the natural product nitrofungin, the antibacterial agent chloroxylenol, and the herbicide chloroxynil. The facile nature of this transformation was demonstrated with the development of one-pot, tandem, iron-catalyzed dihalogenation processes allowing highly regioselective formation of different carbon-halogen bonds. The synthetic utility of the resulting dihalogenated aryl compounds as building blocks was established with the synthesis of natural products and pharmaceutically relevant targets.

Full text of DOI:10.1021/acs.joc.7b01225

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Article
Iron(III)-Catalyzed Chlorination of Activated Arenes
Mohamed A. B. Mostafa, Rosalind M. Bowley, Daugirdas T. Racys, Martyn C. Henry, and Andrew Sutherland
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 29 Jun 2017
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The Journal of Organic Chemistry
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Iron(III)ꢀCatalyzed Chlorination of Activated Arenes
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Mohamed A. B. Mostafa, Rosalind M. Bowley, Daugirdas T. Racys, Martyn C. Henry and Andrew
Sutherland*
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WestCHEM, School of Chemistry, The Joseph Black Building, University of Glasgow,
Glasgow G12 8QQ, United Kingdom.
Andrew.Sutherland@glasgow.ac.uk
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
TITLE RUNNING HEAD: Chlorination of Arenes
CORRESPONDING AUTHOR FOOTNOTE:
University of Glasgow
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Abstract: A general and regioselective method for the chlorination of activated arenes has been
developed. The transformation uses iron(III) triflimide as a powerful Lewis acid for the activation of Nꢀ
chlorosuccinimide and the subsequent chlorination of a wide range of anisole, aniline, acetanilide and
phenol derivatives. The reaction was utilized for the lateꢀstage monoꢀ and diꢀchlorination of a range of
target compounds such as the natural product nitrofungin, the antibacterial agent chloroxylenol and the
herbicide chloroxynil. The facile nature of this transformation was demonstrated with the development
of oneꢀpot tandem ironꢀcatalyzed dihalogenation processes allowing highly regioselective formation of
different carbonꢀhalogen bonds. The synthetic utility of the resulting dihalogenated aryl compounds as
building blocks was established with the synthesis of natural products and pharmaceutically relevant
targets.
Keywords: Chlorination, iron catalysis, Nꢀiodosuccinimide, nitrofungin, chloroxynil.
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INTRODUCTION
Aromatic chlorides are an important class of compounds, widely used in organic chemistry as
synthetic intermediates for coupling or substitution reactions, allowing the preparation of natural
products and medicinally active compounds.1 Due to the relative stability of the carbonꢀchlorine bond,
aryl chlorides are also found as components in a vast array of natural products (e.g. phenols 1–3, Figure
1)2–5 and used as structural motifs in pharmaceuticals, agrochemicals and other biologically active
compounds. Examples include the fungicide nitrofungin (1),3 the broad spectrum antimicrobial agent
chloroxylenol (4)6 and the pesticide chloroxynil (5).7
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Figure 1. Structures of biologically active chlorobenzenes.
Due to the prevalence and importance of aryl chlorides, many general methods are known for the
synthesis of these compounds. In fact, the halogenation of arenes is a fundamental reaction of organic
synthesis. Traditionally, chlorination of aromatic compounds has involved electrophilic aromatic
substitution,8 the Sandmeyer reaction of anilines9 or a directed orthoꢀlithiationꢀchlorination sequence.10
Despite the widespread use of these methods, they can involve harsh conditions, long reaction times and
give poor regioselectivity and control. To overcome these limitations, recent efforts have focused on the
development of new chlorination methods,11 including transition metalꢀcatalyzed reactions.12,13 In
particular, the widespread developments in transition metalꢀcatalyzed chelationꢀdirected aryl CꢀH
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activation have led to a number of methods for orthoꢀchlorination (Scheme 1a).14 Recently, a chelationꢀ
directed aryl CꢀH activation process for metaꢀchlorination was developed by Yu and coꢀworkers using a
palladiumꢀcatalyzed pyridone ligand promoted protocol (Scheme 1b).15
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Scheme 1. Strategies for Regioselective Aryl Chlorination
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We recently reported the use of iron(III) triflimide or silver(I) triflimide as powerful Lewis acids for
Nꢀiodosuccinimide activation and the iodination of aryl compounds for application in radionuclide
imaging.16 This type of transformation was also coupled with a copperꢀcatalyzed Ullmannꢀtype reaction
resulting in a oneꢀpot intermolecular aryl CꢀH amination process.17 We were interested in extending this
Lewis acid catalyzed activation of Nꢀhalosuccinimides for the paraꢀchlorination of arenes, resulting in a
protocol that would be complementary to the many known orthoꢀdirected chlorination methods.
Furthermore, it was proposed that this type of Lewis acid catalyzed chlorination process could be
coupled with other halogenation reactions for the regioselective, oneꢀpot dihalogenation of aromatic
compounds. We now report the development of a general chlorination protocol for paraꢀsubstitution of
activated arenes (Scheme 1c). As well as exploring the scope of this process for the preparation of a
wide range of synthetic building blocks, natural products and pharmaceutically important compounds,
we also describe the development of a tandem iron(III)ꢀcatalyzed chlorinationꢀbromination process for
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the regioselective dihalogenation of aromatic compounds. The synthetic utility of these compounds for
targeted synthesis is also reported.
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RESULTS AND DISCUSSION
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The study began with an investigation of the chlorination of anisole. We have previously shown
iron(III) triflimide catalyzed bromination and iodination of anisole.16a,17 During these transformations,
iron(III) triflimide was generated in situ using iron(III) chloride (5 mol %) and the ionic liquid, 1ꢀbutylꢀ
3ꢀmethylimidazolium bis(trifluoromethylsulfonyl)imide ([BMIM]NTf2), which was also used as the
reaction solvent.18,19 Under the same conditions, it was found that chlorination of anisole (6a) with Nꢀ
chlorosuccinimide (NCS) required more forcing conditions, with a higher temperature of 50 °C (versus
20 °C for iodination), to give 100% conversion after 5 h (Table 1, entry 1). The presence of iron(III)
chloride during this transformation is crucial for activation of NCS, as performing the reaction in the
absence of FeCl3 under the same conditions (50 °C, [BMIM]NTf2 as the solvent) showed no reaction
after 24 h (entry 2).20 While [BMIM]NTf2 is relatively inexpensive, recyclable and imparts high
cohesive pressure to the reaction resulting in fast halogenations, we were interested in developing for
the first time a halogenation reaction that was catalytic in both iron(III) chloride and [BMIM]NTf2. It
was proposed that such a process would allow the chlorination of a wider substrate scope and simpler
work up and isolation protocols. Therefore, a solvent screen was performed using iron(III) chloride (2.5
mol %) and [BMIM]NTf2 (7.5 mol %). Although no conversion was observed using tꢀbutyl methyl ether
(entry 3), good reactivity was noted after 24 h in both toluene and THF (entries 4 and 5). Using THF as
the optimal solvent, an increase in temperature to 60 °C gave complete conversion, combined with a
shorter reaction time of 18 h (entry 6). It was also noted that a doubling of catalyst loading of both
iron(III) trichloride and [BMIM]NTf2 at 60 °C gave a shorter reaction time of 8 h (entry 7). While the
conditions with low catalyst loadings (entry 6) were deemed suitable for most activated aryl
compounds, it was felt necessary to demonstrate the viability of procedures with higher catalyst
loadings (entries 1 and 7), that would likely be required for more challenging substrates.
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Table 1.
Optimization of the Iron-Catalyzed Chlorination of Anisole
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entry FeCl3 (mol %) [BMIM]NTf2 (mol %)
solvent
[BMIM]NTf2
[BMIM]NTf2
tꢀBuOMe
toluene
time (h) temp (°C) conversion (%)a
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ꢀꢀꢀ
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ꢀꢀꢀ
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THF
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THF
aConversions were measured using 1H NMR spectroscopy.
The optimized procedure (Table 1, entry 6) was then used to explore the chlorination of activated
arenes (Scheme 2). In general, the transformation was found to be compatible with a wide range of
functional groups and could be used for the efficient monoꢀchlorination of anisole, phenol, aniline and
acetanilide compounds (7a–7q). In contrast to iodination using iron(III) triflimide where only paraꢀ
products were formed,16a chlorination of several monoꢀsubstituted substrates [e.g. phenol (6f), aniline
(6h) and acetanilide (6m)] yielded the orthoꢀisomer as a byproduct. This is likely due to a combination
of the relatively small size of the chlorinating agent and the more forcing conditions required for this
transformation. Nevertheless, the major paraꢀisomers were easily separated and isolated in good yields
(53–78%). For diꢀ, triꢀ and tetraꢀsubstituted substrates, only the paraꢀchlorinated products were formed,
as observed by NMR spectroscopy of the crude reaction mixture. Similarly, for compounds with the
paraꢀpositioned blocked, orthoꢀchlorinated compounds were cleanly formed in high yield and as single
regioisomers. While the optimized procedure (2.5 mol % of FeCl3) was effective for most substrates,
including 6k bearing the deactivating paraꢀnitro group, several other aryl compounds containing
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strongly electron withdrawing groups (e.g. 6j and 6l) required higher catalyst loading of both FeCl3 (5
mol %) and [BMIM]NTf2 (15 mol %) and a higher reaction temperature (70 °C) for efficient
chlorination. Other arenes, such as naphthalenes 6n–6p and 2,3ꢀdihydrobenzofuran (6q) were also
chlorinated, yielding single regioisomers in high yields. As well as using this method for the preparation
of antiseptic agent chloroxylenol (4),6 reaction of phenol (6f) with two equivalents of NCS allowed
efficient dichlorination and the synthesis of 2,4ꢀdichlorophenol (2), a compound isolated from soil
Penicillium, that is used as a growth hormone and as an intermediate for the preparation of herbicides.4
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Scheme 2. Scope of Iron(III) Triflimide Catalyzed Chlorinationa
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aIsolated yields are shown. Orthoꢀchlorinated products were observed (20% for 6f, mꢀxylenol and
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6m; 30% for 6h). Reaction was performed at 70 °C, using iron(III) trichloride (5 mol %) and
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A number of aryl compounds with deactivating groups gave poor or modest conversion when using
the procedures involving catalytic [BMIM]NTf2. Therefore, an alternative procedure was utilized for the
chlorination of these compounds. It was found that using FeCl3 (5 mol %) and [BMIM]NTf2 as the
solvent, at 70 °C, gave complete conversion to the monoꢀchlorinated products (1, 5 and 7r–7u, Scheme
3). While the reactions required relatively long reaction times, the products were cleanly isolated in high
yields. This allowed the efficient synthesis of 3ꢀchloroꢀ4ꢀmethoxybenzaldehyde (7s),21 a major
metabolite from soil Lepista nuda, as well as nitrofungin (1), a compound isolated from Stephanospora
caroticolor, which was previously used as a fungicide.3 These conditions were also effective for the
dichlorination of 4ꢀhydroxybenzonitrile, producing the pesticide chloroxynil (5) in 73% yield.7
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a
Scheme 3. Iron(III) Triflimide Catalyzed Chlorination in [BMIM]NTf2
aIsolated yields are shown.
The examination of the scope of this protocol clearly demonstrated that iron(III) triflimide catalyzed
chlorination, compared to bromination or iodination, required higher temperatures and longer reaction
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times. This was expected due to the stronger NꢀCl bond of NCS. It was decided to take advantage of the
reactivity difference and the clean production of halogenated products, to use this protocol for the
design of oneꢀpot multistep halogenation processes. It was proposed that a single loading of iron(III)ꢀ
triflimide could be used to catalyze multiple halogenation reactions, allowing the selective preparation
of carbonꢀhalogen bonds with high regiocontrol. It was believed that the products of such a process
could be exploited by using the differences in reactivity of the carbonꢀhalogen bonds to introduce
further functionality. As a proof of concept, anisole (6a) was subjected to a bromination reaction,
followed by chlorination (Scheme 4). Using iron(III) chloride (5 mol %) in [BMIM]NTf2 as the solvent,
at 40 °C gave the paraꢀbrominated product after 1.5 h. Addition of NCS to the reaction mixture and an
increase in temperature to 70 °C, allowed complete orthoꢀchlorination after 24 h and the isolation of 8
in 89% yield. The order of halogenation could also be reversed. Chlorination at higher temperature (60
°C), followed by bromination at 40 °C gave 2ꢀbromoꢀ4ꢀchloroanisole (9) in 81% yield. The highly
regioselective, clean generation of both the intermediate and the final product allowed the scale up of
this process and the multigram synthesis of 9.
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Scheme 4. Tandem Iron(III)-Catalyzed Regioselective Dihalogenationa
aIsolated yields are shown.
Having used the tandem iron(III)ꢀcatalyzed halogenation process for the oneꢀpot synthesis of 9, we
wanted to demonstrate the synthetic utility of such compounds, in particular, for the selective
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functionalization of the C–Br bond and the preparation of biologically relevant chlorobenzene targets. 2ꢀ
Bromoꢀ4ꢀchloroanisole (9) was found to be a good substrate for copper(I)ꢀcatalyzed Nꢀarylation
reactions (Scheme 5). Using 4ꢀchlorobenzenesulfonamide as the nucleophile gave 10, a compound with
antibacterial activity, in 65% yield.22 A similar copper(I)ꢀcatalyzed Nꢀarylation reaction with
benzenesulfonamide, followed by Nꢀmethylation gave cholinesterase inhibitor 12 in good overall
yield.23 2ꢀBromoꢀ4ꢀchloroanisole (9) was also used for a novel synthesis of helitenuone (3), a thiopheneꢀ
derived chlorophenol isolated from Helichrysum species.5 The only other synthesis of this natural
product involved a sixꢀstep sequence from a chlorinated benzaldehyde derivative, which gave
helitenuone (3) in 7% overall yield.5b In this current study, 2ꢀbromoꢀ4ꢀchloroanisole (9) was subjected
to a SuzukiꢀMiyaura reaction with commercially available thiopheneꢀderived boronic acid 13, under
standard conditions. This gave coupled product 14 in 79% yield. Deprotection of the phenol moiety
using boron tribromide completed the threeꢀpot synthesis of helitenuone (3) in 56% overall yield from
anisole (6a).
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Scheme 5. Synthetic Applications of 2-Bromo-4-chloroanisole (9)a
aIsolated yields are shown.
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CONCLUSIONS
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In summary, methods for the chlorination of arenes using iron(III) triflimide activation of NCS have
been developed. In particular, a procedure that utilizes catalytic amounts of both iron(III) chloride and
[BMIM]NTf2 was optimised for the regioselective monoꢀchlorination of activated arene substrates,
while the use of higher loadings and the ionic liquid as a solvent was effective for more deactivated
aromatic compounds. The reactions were also extended for dihalogenation, including the development
of a selective oneꢀpot tandem iron(III)ꢀcatalyzed process where different halogens could be introduced
in a highly regioselective manner. The synthetic utility of both the singleꢀstep chlorination and the oneꢀ
pot dihalogenations has been demonstrated with the rapid and efficient synthesis of a range of
chlorobenzeneꢀcontaining natural products and biologically active targets. In particular, the threeꢀpot
regioselective synthesis of helitenuone (3) demonstrates how highly functional aromatic compounds can
be quickly accessed using these methods. Further studies to extend these strategies and concepts for the
synthesis of other halogenated arenes are currently underway.
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EXPERIMENTAL SECTION
All reagents and starting materials were obtained from commercial sources and used as received. The
iron(III) chloride used in this study is reagent grade (97%). All dry solvents were purified using a
solvent purification system. All reactions were performed under an atmosphere of argon unless
otherwise mentioned. Brine refers to a saturated solution of sodium chloride. Flash column
chromatography was performed using silica gel 60 (35–70 µm). Aluminiumꢀbacked plates preꢀcoated
with silica gel 60F254 were used for thin layer chromatography and were visualized with a UV lamp or
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by staining with potassium permanganate. H NMR spectra were recorded on a NMR spectrometer at
either 400 or 500 MHz and data are reported as follows: chemical shift in ppm relative to
tetramethylsilane as the internal standard, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m
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= multiplet or overlap of nonequivalent resonances, integration). C NMR spectra were recorded on a
NMR spectrometer at either 101 or 126 MHz and data are reported as follows: chemical shift in ppm
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relative to tetramethylsilane or the solvent (CDCl3, δ 77.0 ppm or DMSOꢀd6, δ 39.5 ppm) as internal
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standard, multiplicity with respect to hydrogen (deduced from DEPT experiments, C, CH, CH2 or CH3).
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Conversions (Table 1) were measured by H NMR spectroscopy, using dimethyl sulfone as an internal
standard. Infrared spectra were recorded on a FTIR spectrometer; wavenumbers are indicated in cm–1.
Mass spectra were recorded using electron impact, chemical ionization or electrospray techniques.
HRMS spectra were recorded using a dualꢀfocusing magnetic analyzer mass spectrometer. Melting
points are uncorrected.
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General Chlorination Procedure A. Iron(III) chloride (0.0250 mmol) was dissolved in 1ꢀbutylꢀ3ꢀ
methylimidazolium bis(trifluoromethanesulfonyl)imide (0.0750 mmol), stirred for 0.5 h at room
temperature and then added to a solution of Nꢀchlorosuccinimide (1.05 mmol) in tetrahydrofuran (0.6
mL) under an atmosphere of air. The substrate (1.00 mmol) was then added and the reaction mixture
was heated to 60 °C, resulting in a homogeneous solution. Upon completion, the reaction mixture was
cooled to room temperature, diluted with ethyl acetate (10 mL) and washed with a 1 M sodium
thiosulfate solution (10 mL) and brine (10 mL). The organic phase was dried (MgSO4), filtered and
concentrated in vacuo. The crude product was purified by flash column chromatography.
General Chlorination Procedure B. NꢀChlorosuccinimide (1.05 mmol) was added to a solution of
iron(III) chloride (0.0500 mmol) in 1ꢀbutylꢀ3ꢀmethylimidazolium bis(trifluoromethanesulfonyl)imide
(0.3 mL) under an atmosphere of air. The mixture was stirred at room temperature for 0.5 h before the
substrate (1.00 mmol) in acetonitrile (0.1 mL) was added. The reaction mixture was heated to 70 °C
resulting in a homogeneous mixture. Upon completion, the reaction mixture was then extracted with 5%
ethyl acetate in hexane (3 × 50 mL) using sonication in a water bath for 0.1 h. The suspension was
washed with an aqueous solution of 1 M sodium thiosulfate (10 mL), brine (10 mL), dried (MgSO4) and
then filtered through a pad of Celite®. The solvent was removed under reduced pressure and the crude
product was purified by flash column chromatography.
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Work Up for Carboxylic acids and phenol derivatives. The reaction mixture was diluted with
dichloromethane (10 mL) and extracted with an aqueous solution of 1 M sodium hydroxide (20 mL).
The aqueous phase was separated, acidified with 1 M hydrochloric acid and extracted with
dichloromethane (2 × 50 mL). The organic phase was dried over MgSO4, filtered and the solvent was
removed under reduced pressure. The crude product was purified by flash column chromatography.
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4-Chloroanisole (7a).24 The reaction was performed as described in general procedure A using
anisole (6a) (108 ꢁL, 1.00 mmol). The reaction mixture was heated to 60 °C for 18 h. Purification by
flash column chromatography (petroleum ether/ethyl acetate, 19:1) gave 4ꢀchloroanisole (7a) (131 mg,
92%) as a colorless oil. Spectroscopic data were consistent with the literature.24 1H NMR (500 MHz,
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CDCl3) δ 3.77 (s, 3H), 6.80–6.85 (m, 2H), 7.21–7.26 (m, 2H); C NMR (126 MHz, CDCl3) δ 55.5
(CH3), 115.2 (2 × CH), 125.5 (C), 129.3 (2 × CH), 158.2 (C); MS (EI) m/z 142 (M+, 100), 127 (46), 99
(39), 84 (16).
4-Chloro-2-methylanisole (7b).25 The reaction was performed as described in general procedure A
using 2ꢀmethylanisole (6b) (124 ꢁL, 1.00 mmol). The reaction mixture was heated to 60 °C for 24 h.
Purification by flash column chromatography (petroleum ether/ethyl acetate, 4:1) gave 4ꢀchloroꢀ2ꢀ
methylanisole (7b) (133 mg, 85%) as a yellow oil. Spectroscopic data were consistent with the
literature.25 1H NMR (400 MHz, CDCl3) δ 2.21 (s, 3H), 3.81 (s, 3H), 6.73 (d, J = 9.2 Hz, 1H), 7.09–7.15
13
(m, 2H); C NMR (101 MHz, CDCl3) δ 16.2 (CH3), 55.6 (CH3), 111.1 (CH), 125.1 (C), 126.4 (CH),
128.6 (C), 130.5 (CH), 156.5 (C); MS (EI) m/z 156 (M+, 100), 141 (63), 83 (35), 77 (45), 57 (38).
5-Chloro-2,4-dimethoxybenzaldehyde (7c).26 The reaction was performed as described in general
procedure A using 2,4ꢀdimethoxybenzaldehyde (6c) (166 mg, 1.00 mmol). The reaction mixture was
heated to 60 °C for 24 h. Purification by flash column chromatography (petroleum ether/ethyl acetate,
10:1) gave 5ꢀchloroꢀ2,4ꢀdimethoxybenzaldehyde (7c) (154 mg, 77%) as a white solid. Spectroscopic
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data were consistent with the literature.26 Mp 130–132 °C; H NMR (500 MHz, CDCl3) δ 3.93 (s, 3H),
3.97 (s, 3H), 6.46 (s, 1H), 7.81 (s, 1H), 10.23 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 56.0 (CH3), 56.4
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(CH3), 95.7 (CH), 115.3 (C), 118.7 (C), 129.7 (CH), 160.8 (C), 162.4 (C), 187.2 (CH); MS (ESI) m/z
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223 (MNa+, 100).
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5-Chloro-2,4-dimethoxybenzoic acid (7d). The reaction was performed as described in general
procedure A using 2,4ꢀdimethoxybenzoic acid (6d) (182 mg, 1.00 mmol). The reaction mixture was
heated to 60 °C for 24 h. Purification by flash column chromatography (dichloromethane/methanol,
19:1) gave 5ꢀchloroꢀ2,4ꢀdimethoxybenzoic acid (7d) (181 mg, 84%) as a white solid. Mp 166–168 °C.
IR (neat) 2970, 2569, 1694, 1599, 1243, 1213, 1021, 904, 820, 727 cm−1; 1H NMR (500 MHz, CDCl3) δ
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3.98 (s, 3H), 4.08 (s, 3H), 6.53 (s, 1H), 8.13 (s, 1H); C NMR (126 MHz, CDCl3) δ 56.6 (CH3), 57.1
(CH3), 96.0 (CH), 110.6 (C), 116.1 (C), 134.5 (CH), 158.4 (C), 160.0 (C), 164.6 (C); MS (EI) m/z 218
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(M+, 36), 216 (100), 199 (47), 169 (42), 142 (22), 78 (27), 63 (32); HRMS (EI) calcd for C9H9 ClO4
(M+) 218.0163, found 218.0167.
5-Chloro-2,4-dimethoxy-6-hydroxybenzaldehyde (7e). The reaction was performed as described in
general procedure A using 2,4ꢀdimethoxyꢀ6ꢀhydroxybenzaldehyde (6e) (182 mg, 1.00 mmol). The
reaction mixture was heated to 60 °C for 18 h. Purification by flash column chromatography (petroleum
ether/ethyl acetate, 7:3) gave 5ꢀchloroꢀ2,4ꢀdimethoxyꢀ6ꢀhydroxybenzaldehyde (7e) (182 mg, 84%) as a
light yellow solid. Mp 184–186 °C; IR (neat) 2953, 1631, 1595, 1470, 1453, 1417, 1410, 1292, 1227,
1186, 1119, 1100, 790, 731 cm−1; 1H NMR (500 MHz, CDCl3) δ 3.91 (s, 3H), 3.97 (s, 3H), 5.99 (s, 1H),
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10.09 (s, 1H), 12.80 (s, 1H); C NMR (126 MHz, CDCl3) δ 56.0 (CH3), 56.5 (CH3), 86.7 (CH), 101.4
(C), 106.1 (C), 160.3 (C), 162.5 (C), 162.8 (C), 192.0 (CH); MS (ESI) m/z 239 (MNa+, 100); HRMS
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(ESI) calcd for C9H9 ClNaO4 (MNa+) 239.0082, found 239.0083.
4-Chlorophenol (7f).27 The reaction was performed as described in general procedure A using phenol
(6f) (94 mg, 1.0 mmol). The reaction mixture was heated to 60 °C for 18 h. Purification by flash column
chromatography (petroleum ether/ethyl acetate, 19:1) gave 4ꢀchlorophenol (7f) (96 mg, 75%) as a
colorless oil. Spectroscopic data were consistent with the literature.27 1H NMR (500 MHz, CDCl3) δ
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4.77 (br s, 1H), 6.74–6.79 (m, 2H), 7.17–7.22 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 116.7 (2 × CH),
125.8 (C), 129.5 (2 × CH), 154.0 (C); MS (EI) m/z 128 (M+, 100), 102 (34), 84 (90), 66 (98), 57 (27).
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4-Chloro-2-methylphenol (7g).28 The reaction was performed as described in general procedure A
using 2ꢀmethylphenol (6g) (108 mg, 1.00 mmol). The reaction mixture was heated to 60 °C for 12 h.
Purification by flash column chromatography (petroleum ether/ethyl acetate, 19:1) gave 4ꢀchloroꢀ2ꢀ
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methylphenol (7g) (115 mg, 81%) as a yellow solid. Mp 46–48 °C (lit.28 46–47 °C); H NMR (500
MHz, CDCl3) δ 2.22 (s, 3H), 5.02 (br s, 1H), 6.69 (d, J = 8.5 Hz, 1H), 7.03 (dd, J = 8.5, 2.7 Hz, 1H),
7.10 (d, J = 2.7 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 15.7 (CH3), 116.1 (CH), 125.3 (C), 125.8 (C),
126.8 (CH), 130.7 (CH), 152.3 (C); MS (CI) m/z 143 (MH+, 48), 113 (45), 97 (40), 85 (68), 71 (100), 69
(54).
4-Chloro-3,5-dimethylphenol (4).29 The reaction was performed as described in general procedure A
using 3,5ꢀdimethylphenol (122 mg, 1.00 mmol). The reaction mixture was heated to 60 °C for 12 h.
Purification by flash column chromatography (petroleum ether/ethyl acetate, 19:1) gave 4ꢀchloroꢀ3,5ꢀ
dimethylphenol (4) (119 mg, 76%) as a white solid. Mp 112–114 °C (lit.29 116 °C); 1H NMR (500 MHz,
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CDCl3) δ 2.32 (s, 6H), 4.72 (s, 1H), 6.58 (s, 2H); C NMR (126 MHz, CDCl3) δ 20.8 (2 × CH3), 115.3
(2 × CH), 126.3 (C), 137.4 (2 × C), 153.2 (C); MS (CI) m/z 157 (MH+, 26), 113 (66), 97 (43), 85 (69),
71 (100), 69 (53).
4-Chloroaniline (7h).30 The reaction was performed as described in general procedure A using
aniline (6h) (91 ꢁL, 1.0 mmol). The reaction mixture was heated to 40 °C for 24 h. Purification by flash
column chromatography (petroleum ether/ethyl acetate, 19:1) gave 4ꢀchloroaniline (7h) (67 mg, 53%)
as a yellow solid. Mp 58–60 °C (lit.30 63–65 °C); 1H NMR (400 MHz, CDCl3) δ 3.64 (br s, 2H), 6.56–
6.65 (m, 2H), 7.07–7.14 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 116.3 (2 × CH), 123.3 (C), 129.2 (2 ×
CH), 145.1 (C); MS (EI) m/z 127 (M+, 100), 92 (16), 84 (19), 64 (19).
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4-Chloro-2-fluoroaniline (7i).31 The reaction was performed as described in general procedure A
using 2ꢀfluoroaniline (6i) (111 mg, 1.00 mmol). The reaction mixture was heated to 60 °C for 18 h.
Purification by flash column chromatography (petroleum ether/ethyl acetate, 19:1) gave 4ꢀchloroꢀ2ꢀ
fluoroaniline (7i) (109 mg, 75%) as a brown oil. Spectroscopic data were consistent with the literature.31
1H NMR (500 MHz, CDCl3) δ 3.70 (br s, 2H), 6.69 (dd, J = 9.4, 8.5 Hz, 1H), 6.92 (ddd, J = 8.5, 2.3, 1.2
Hz, 1H), 7.00 (dd, J = 10.8, 2.3 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 115.9 (CH, d, 2JCF = 22.0 Hz),
117.3 (CH, d, 3JCF = 4.4 Hz), 122.5 (C, d, 3JCF = 9.2 Hz), 124.5 (CH, d, 4JCF = 3.6 Hz), 133.3 (C, d, 2JCF
= 13.0 Hz), 151.2 (C, d, 1JCF = 242.3 Hz); MS (EI) m/z 145 (M+, 32), 84 (100).
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4-Chloro-2-trifluoromethylaniline (7j).32 The reaction was performed as described in general
procedure A using 2ꢀtrifluoromethylaniline (6j) (126 ꢁL, 1.00 mmol), iron(III) chloride (8.00 mg,
0.0500 mmol) and [BMIM]NTf2 (44.0 ꢁL, 0.150 mmol) in tetrahydrofuran (600 ꢁL). The reaction
mixture was heated to 70 °C for 24 h. Purification by flash column chromatography (petroleum
ether/ethyl acetate, 7:3) gave 4ꢀchloroꢀ2ꢀtrifluoromethylaniline (7j) (139 mg, 71%) as a pale yellow oil.
Spectroscopic data were consistent with the literature.32 1H NMR (500 MHz, CDCl3) δ 4.17 (br s, 2H),
6.67 (d, J = 8.7 Hz, 1H), 7.24 (dd, J = 8.7, 2.4 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H); 13C NMR (126 MHz,
CDCl3) δ 114.8 (C, q, 2JCF = 30.8 Hz), 118.4 (CH), 122.4 (C), 124.1 (C, q, 1JCF = 272.4 Hz), 126.3 (CH,
3
q, JCF = 5.5 Hz), 132.8 (CH), 143.1 (C); MS (EI) m/z 195 (M+, 59), 175 (45), 148 (36), 107 (19), 84
(100), 77 (46).
2-Chloro-4-nitroaniline (7k).33 The reaction was performed as described in general procedure A
using 4ꢀnitroaniline (6k) (138 mg, 1.00 mmol). The reaction mixture was heated to 60 °C for 24 h.
Purification by flash column chromatography (petroleum ether/ethyl acetate, 9:1) gave 2ꢀchloroꢀ4ꢀ
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nitroaniline (7k) (153 mg, 89%) as a yellow solid. Mp 98–100 °C (lit.33 99–101 °C); H NMR (500
MHz, CDCl3) δ 4.85 (br s, 2H), 6.75 (d, J = 8.9 Hz, 1H), 7.98 (dd, J = 8.9, 2.5 Hz, 1H), 8.19 (d, J = 2.5
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Hz, 1H); C NMR (126 MHz, CDCl3) δ 113.7 (CH), 117.7 (C), 124.4 (CH), 126.0 (CH), 138.8 (C),
148.9 (C); MS (EI) m/z 172 (M+, 100), 142 (60), 126 (28), 99 (21), 90 (70), 63 (29).
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4-Amino-3-chlorobenzonitrile (7l).34 The reaction was performed as described in general procedure
A using 4ꢀaminobenzonitrile (6l) (118 mg, 1.00 mmol), iron(III) chloride (8.00 mg, 0.0500 mmol) and
[BMIM]NTf2 (44.0 ꢁL, 0.150 mmol) in tetrahydrofuran (600 ꢁL). The reaction mixture was heated to
70 °C for 24 h. Purification by flash column chromatography (petroleum ether/ethyl acetate, 9:1) gave
4ꢀaminoꢀ3ꢀchlorobenzonitrile (7l) (142 mg, 93%) as a white solid. Mp 102–104 °C (lit.34 105.7–107.9
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°C); H NMR (400 MHz, CDCl3) δ 4.65 (br s, 2H), 6.75 (d, J = 8.4 Hz, 1H), 7.31 (dd, J = 8.4, 1.8 Hz,
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1H), 7.50 (d, J = 1.8 Hz, 1H); C NMR (101 MHz, CDCl3) δ 100.7 (C), 115.1 (CH), 118.5 (C), 119.0
(C), 132.0 (CH), 133.3 (CH), 147.2 (C); MS (EI) m/z 152 (M+, 100), 125 (45), 117 (46), 90 (47), 76
(40), 63 (45).
4-Chloroacetanilide (7m).35 The reaction was performed as described in general procedure A using
acetanilide (6m) (135 mg, 1.00 mmol). The reaction mixture was heated to 60 °C for 24 h. Purification
by flash column chromatography (petroleum ether/ethyl acetate, 4:1) gave 4ꢀchloroacetanilide (7m)
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(132 g, 78%) as a white solid. Mp 174–176 °C (lit.35 175–178 °C); H NMR (500 MHz, CDCl3) δ 2.17
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(s, 3H), 7.21–7.30 (m, 3H), 7.42–7.48 (m, 2H); C NMR (126 MHz, CDCl3) δ 24.6 (CH3), 121.0 (2 ×
CH), 129.0 (2 × CH), 129.3 (C), 136.4 (C), 168.2 (C); MS (ESI) m/z 192 (MNa+, 100).
1-Chloro-4-methoxynaphthalene (7n).36 The reaction was performed as described in general
procedure A using 1ꢀmethoxynaphthalene (6n) (144 ꢁL, 1.00 mmol). The reaction mixture was heated
to 60 °C for 18 h. Purification by flash column chromatography (petroleum ether/ethyl acetate, 19:1)
gave 1ꢀchloroꢀ4ꢀmethoxynaphthalene (7n) (175 mg, 91%) as a colorless oil. Spectroscopic data were
consistent with the literature.36 1H NMR (400 MHz, CDCl3) δ 4.00 (s, 3H), 6.73 (d, J = 8.3 Hz, 1H),
7.46 (d, J = 8.3 Hz, 1H), 7.54 (ddd, J = 8.3, 6.9, 1.3 Hz, 1H), 7.62 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 8.20
13
(br d, J = 8.4 Hz, 1H), 8.29 (br d, J = 8.3 Hz, 1H); C NMR (101 MHz, CDCl3) δ 55.7 (CH3), 103.8
(CH), 122.4 (CH), 123.2 (C), 124.2 (CH), 125.7 (CH), 125.9 (CH), 126.6 (C), 127.5 (CH), 131.3 (C),
154.6 (C); MS (EI) m/z 192 (M+, 100), 177 (52), 149 (66), 114 (14), 84 (46).
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1-Chloro-2-methoxynaphthalene (7o).11a The reaction was performed as described in general
procedure A using 2ꢀmethoxynaphthalene (6o) (158 mg, 1.00 mmol), iron(III) chloride (8.00 mg,
0.0500 mmol) and [BMIM]NTf2 (44.0 ꢁL, 0.150 mmol) in tetrahydrofuran (600 ꢁL). The reaction
mixture was heated to 70 °C for 18 h. Purification by flash column chromatography (petroleum
ether/ethyl acetate, 19:1) gave 1ꢀchloroꢀ2ꢀmethoxynaphthalene (7n) (173 mg, 90%) as a white solid. Mp
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64–66 °C (lit.11a 68–69 °C); H NMR (400 MHz, CDCl3) δ 4.03 (s, 3H), 7.29 (d, J = 9.0 Hz, 1H), 7.41
(ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.58 (ddd, J = 8.4, 6.8, 1.2 Hz, 1H), 7.77 (d, J = 9.0 Hz, 1H), 7.80 (br d,
J = 8.2 Hz, 1H), 8.21–8.26 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 57.1 (CH3), 113.8 (CH), 117.0 (C),
123.6 (CH), 124.4 (CH), 127.6 (CH), 128.1 (2 × CH), 129.6 (C), 132.0 (C), 152.7 (C); MS (EI) m/z 192
(M+, 27), 149 (25), 97 (18), 84 (91), 66 (100), 57 (43).
1-Chloro-2-naphthol (7p).37 The reaction was performed as described in general procedure A using
2ꢀnaphthol (6p) (144 mg, 1.00 mmol). The reaction mixture was heated to 60 °C for 18 h. Purification
by flash column chromatography (petroleum ether/ethyl acetate, 9:1) gave 1ꢀchloroꢀ2ꢀnaphthol (7p)
(174 mg, 97%) as an offꢀwhite solid. Mp 64–66 °C (lit.37 66 °C); 1H NMR (500 MHz, CDCl3) δ 5.87 (s,
1H), 7.26 (d, J = 8.9 Hz, 1H), 7.40 (ddd, J = 8.1, 6.8, 1.1 Hz, 1H), 7.57 (ddd, J = 8.5, 6.8, 1.2 Hz, 1H),
7.71 (d, J = 8.9 Hz, 1H), 7.79 (br d, J = 8.1 Hz, 1H), 8.06 (br d, J = 8.5 Hz, 1H); 13C NMR (126 MHz,
CDCl3) δ 113.4 (C), 117.3 (CH), 122.8 (CH), 124.2 (CH), 127.6 (CH), 128.2 (CH), 128.5 (CH), 129.5
(C), 131.1 (C), 149.4 (C); MS (ESI) m/z 177 ([MꢀH]−, 100).
5-Chloro-2,3-dihydrobenzofuran (7q).38 The reaction was performed as described in general
procedure A using 2,3ꢀdihydrobenzofuran (6q) (113 ꢁL, 1.00 mmol). The reaction mixture was heated
to 60 °C for 18 h. Purification by flash column chromatography (petroleum ether/ethyl acetate, 9:1)
gave 5ꢀchloroꢀ2,3ꢀdihydrobenzofuran (7q) (133 mg, 86%) as a colorless oil. Spectroscopic data were
consistent with the literature.38 1H NMR (500 MHz, CDCl3) δ 3.20 (t, J = 8.7 Hz, 2H), 4.58 (t, J = 8.7
Hz, 2H), 6.69 (d, J = 8.4 Hz, 1H), 7.05 (dd, J = 8.4, 2.2 Hz, 1H), 7.13–7.16 (m, 1H, m); 13C NMR (126
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MHz, CDCl3) δ 29.7 (CH2), 71.6 (CH2), 110.2 (CH), 125.0 (C and CH), 127.8 (CH), 128.9 (C), 158.7
(C); MS (EI) m/z 154 (M+, 80), 91 (41), 84 (100).
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2,4-Dichlorophenol (2).39 The reaction was performed as described in general procedure A using
phenol (6f) (94.0 mg, 1.00 mmol), NCS (280 mg, 2.10 mmol) in tetrahydrofuran (1.2 mL). The reaction
mixture was heated to 60 °C for 48 h. Purification by flash column chromatography (petroleum
ether/diethyl ether 19:1) gave 2,4ꢀdichlorophenol (2) (131 mg, 81%) as a light orange solid. Mp 40–42
°C (lit.39 43–44 °C); 1H NMR (400 MHz, CDCl3) δ 5.49 (s, 1H), 6.95 (d, J = 8.7 Hz, 1H), 7.15 (dd, J =
8.7, 2.5 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 117.3 (CH), 120.6 (C), 125.8
(C), 128.7 (2 × CH), 150.4 (C); MS (EI) m/z 162 (M+, 100), 153 (21), 136 (18), 107 (46), 89 (38).
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5-Chloro-2-methoxybenzaldehyde (7r).40 The reaction was performed as described in general
procedure B using 2ꢀmethoxybenzaldehyde (6r) (60 mg, 0.44 mmol). The reaction mixture was heated
to 70 °C for 18 h. Purification by flash column chromatography (petroleum ether/ethyl acetate, 9:1)
gave 5ꢀchloroꢀ2ꢀmethoxybenzaldehyde (7r) (51 mg, 68%) as a white solid. Mp 78–79 °C (lit.40 80–81
°C); 1H NMR (400 MHz, CDCl3) δ 3.93 (s, 3H), 6.95 (d, J = 8.9 Hz, 1H), 7.50 (dd, J = 8.9, 2.8 Hz, 1H),
13
7.79 (d, J = 2.8 Hz, 1H), 10.41 (s, 1H); C NMR (126 MHz, CDCl3) δ 56.0 (CH3), 113.3 (CH), 125.7
(C), 126.4 (C), 128.0 (CH), 135.4 (CH), 160.3 (C), 188.5 (CH); MS (EI) m/z 170 (M+, 17), 153 (6), 84
(100), 49 (79), 44 (32).
3-Chloro-4-methoxybenzaldehyde (7s).41 The reaction was performed as described in general
procedure B using 4ꢀmethoxybenzaldehyde (6s) (122 ꢁL, 1.00 mmol) and NCS (160 mg, 1.20 mmol).
The reaction mixture was heated to 70 °C for 18 h. Purification by flash column chromatography
(petroleum ether/ethyl acetate 19:1) gave 3ꢀchloroꢀ4ꢀmethoxybenzaldehyde (7s) (141 mg, 83%) as a
pale yellow solid. Mp 52–54 °C (lit.41 53–55 °C); 1H NMR (400 MHz, CDCl3) δ 3.99 (s, 3H), 7.04 (d, J
13
= 8.5 Hz, 1H), 7.77 (dd, J = 8.5, 2.0 Hz, 1H), 7.91 (d, J = 2.0 Hz, 1H), 9.85 (s, 1H); C NMR (101
MHz, CDCl3) δ 56.5 (CH3), 111.7 (CH), 123.7 (C), 130.3 (C), 130.5 (CH), 131.2 (CH), 159.8 (C), 189.6
(CH); MS (EI) m/z 169 (M+, 100), 143 (13), 126 (15), 115 (19), 99 (14), 83 (16), 75 (12), 63 (26).
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3-Chloro-4-methoxybenzoic acid (7t).42 The reaction was performed as described in general
procedure B using 4ꢀmethoxybenzoic acid (6t) (76 mg, 0.50 mmol). The reaction mixture was heated to
70 °C for 24 h. Purification by flash column chromatography (petroleum ether/ethyl acetate, 17:3) gave
3ꢀchloroꢀ4ꢀmethoxybenzoic acid (7t) (86 mg, 92%) as a white solid. Mp 208–210 °C (lit.42 211–214
°C); 1H NMR (400 MHz, CDCl3) δ 3.99 (s, 3H), 6.99 (d, J = 8.7 Hz, 1H), 8.02 (dd, J = 8.7, 2.1 Hz, 1H),
8.13 (d, J = 2.1 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 56.6 (CH3), 111.5 (CH), 122.4 (C), 122.9 (C),
130.8 (CH), 132.5 (CH), 159.5 (C), 170.0 (C); MS (EI) m/z 186 (M+, 83), 169 (41), 115 (13), 83 (100),
63 (11).
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2-Chloro-4-nitrophenol (1).43 The reaction was performed as described in general procedure B using
4ꢀnitrophenol (70 mg, 0.50 mmol). The reaction mixture was heated to 70 °C for 48 h. Purification by
flash column chromatography (petroleum ether/ethyl acetate 3:1) gave 2ꢀchloroꢀ4ꢀnitrophenol (1) (64
mg, 74%) as a yellow solid. Mp 108–110 °C (lit.43 110–112 °C); 1H NMR (400 MHz, CDCl3) δ 6.34 (s,
13
1H), 7.13 (d, J = 9.0 Hz, 1H), 8.12 (dd, J = 9.0, 2.7 Hz, 1H), 8.29 (d, J = 2.7 Hz, 1H); C NMR (101
MHz, CDCl3) δ 116.4 (CH), 120.5 (C), 124.7 (CH), 125.5 (CH), 141.7 (C), 157.0 (C); MS (EI) m/z 173
(M+, 100), 143 (39), 107 (21), 99 (37), 84 (65), 63 (36).
N-(2-Acetyl-4-chlorophenyl)acetamide (7u). The reaction was performed as described in general
procedure B using Nꢀ(2ꢀacetylphenyl)acetamide (6u) (99 mg, 0.50 mmol). The reaction mixture was
heated to 70 °C for 48 h. Purification by flash column chromatography (petroleum ether/diethyl ether,
9:1) gave Nꢀ(2ꢀacetylꢀ4ꢀchlorophenyl)acetamide (7u) (101 mg, 95%) as a white solid. Mp 126–128 °C;
IR (neat) 3218, 2359, 1685, 1657, 1588, 1501, 1400, 1360, 1311, 1286, 1246, 1224, 828, 773, 637 cm−1;
1H NMR (400 MHz, CDCl3) δ 2.22 (s, 3H), 2.65 (s, 3H), 7.49 (dd, J = 9.1, 2.5 Hz, 1H), 7.82 (d, J = 2.5
13
Hz, 1H), 8.72 (d, J = 9.1 Hz, 1H), 11.56 (br s, 1H); C NMR (101 MHz, CDCl3) δ 25.6 (CH3), 28.7
(CH3), 122.4 (CH), 122.9 (C), 127.3 (C), 131.2 (CH), 135.0 (CH), 139.7 (C), 169.6 (C), 201.9 (C); MS
(EI) m/z 211 (M+, 44), 169 (97), 154 (100); HRMS (EI) calcd for C10H1035ClNO2 (M+) 211.0400, found
211.0402.
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3,5-Dichloro-4-hydroxybenzonitrile (5). The reaction was performed as described in general
procedure B using 4ꢀhydroxybenzonitrile (60.0 mg, 0.500 mmol), NCS (147 mg, 1.10 mmol). The
reaction mixture was heated to 70 °C and stirred for 36 h. Purification by flash column chromatography
(petroleum ether/ethyl acetate, 7:3) gave 3,5ꢀdichloroꢀ4ꢀhydroxybenzonitrile (5) (68 mg, 73%) as a
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white solid. Mp 128–130 °C; IR (neat) 3255, 2924, 2243, 1483, 1302, 1150, 909 cm−1; H NMR (400
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MHz, CDCl3) δ 6.48 (br s, 1H), 7.59 (s, 2H); 13C NMR (101 MHz, CDCl3) δ 105.4 (C), 116.7 (C), 122.3
35
(2 × C), 132.2 (2 × CH), 152.3 (C); MS (EI) m/z 187 (M+, 100); HRMS (EI) calcd for C7H3 Cl2NO
(M+) 186.9592, found 186.9583.
4-Bromo-2-chloroanisole (8).44 NꢀBromosuccinimide (178 mg, 1.00 mmol) was added to a solution
of iron(III) chloride (8.00 mg, 0.0500 mmol) in [BMIM]NTf2 (0.40 mL) under an atmosphere of air.
The mixture was stirred at room temperature for 0.5 h before anisole (6a) (108 ꢁL, 1.00 mmol) in
acetonitrile (0.10 mL) was added. The reaction mixture was heated to 40 °C for 1.5 h. The reaction
mixture was cooled to room temperature and Nꢀchlorosuccinimide (160 mg, 1.20 mmol) was then
added. The reaction mixture was heated to 70 °C for 24 h. The reaction was worked up according to
general chlorination procedure B. Purification by flash column chromatography (petroleum ether/ethyl
acetate, 19:1) gave 4ꢀbromoꢀ2ꢀchloroanisole (8) (197 mg, 89%) as a pale yellow solid. Mp 66–68 °C
(lit.44 66.5–68.2 °C); 1H NMR (400 MHz, CDCl3) δ 3.88 (s, 3H), 6.79 (d, J = 8.8 Hz, 1H), 7.33 (dd, J =
8.8, 2.4 Hz, 1H), 7.50 (d, J = 2.4 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 56.3 (CH3), 112.5 (C), 113.3
(CH), 123.7 (C), 130.5 (CH), 132.7 (CH), 154.4 (C); MS (EI) m/z 222 (M+, 86), 179 (100), 126 (36).
2-Bromo-4-chloroanisole (9).45 The reaction was performed as described in general procedure B
using anisole (6a) (108 ꢁL, 1.00 mmol). The reaction mixture was heated to 60 °C for 6 h. On
completion of the chlorination step, the reaction mixture was cooled to room temperature and Nꢀ
bromosuccinimide (178 mg, 1.00 mmol) was then added. The reaction mixture was heated to 40 °C for
18 h. Purification by flash column chromatography (petroleum ether/ethyl acetate, 17:3) gave 2ꢀbromoꢀ
4ꢀchloroanisole (9) (178 mg, 81%) as a colorless oil. Spectroscopic data were consistent with the
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literature.45 1H NMR (500 MHz, CDCl3) δ 3.88 (s, 3H), 6.82 (d, J = 8.8 Hz, 1H), 7.24 (dd, J = 8.8, 2.5
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Hz, 1H), 7.54 (d, J = 2.5 Hz, 1H); C NMR (126 MHz, CDCl3) δ 56.6 (CH3), 112.3 (C), 112.7 (CH),
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126.1 (C), 128.4 (CH), 132.9 (CH), 154.9 (C); MS (EI) m/z 222 (M+, 100), 207 (50), 179 (36), 126 (10),
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75 (12), 63 (21).
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N-(5’-Chloro-2’-methoxyphenyl)-4-chlorobenzenesulfonamide (10).22 To a solution of 2ꢀbromoꢀ4ꢀ
chloroanisole (9) (110 mg, 0.500 mmol) in toluene (0.50 mL) was added 4ꢀchlorobenzenesulfonamide
(115 mg, 0.600 mmol), copper(I) iodide (10.0 mg, 0.0500 mmol), N,N′ꢀdimethylethylenediamine (11.0
ꢁL, 0.100 mmol), cesium carbonate (326 mg, 1.00 mmol) and water (0.30 mL). The reaction mixture
was degassed under argon for 0.1 h and then heated to 150 °C for 24 h. The reaction mixture was then
cooled to room temperature, diluted with ethyl acetate (10 mL), washed with 1 M sodium thiosulfate
solution (10 mL) and brine (10 mL). The organic phase was dried (MgSO4), filtered and concentrated in
vacuo. Purification by flash column chromatography (petroleum ether/ethyl acetate, 4:1) gave Nꢀ(5’ꢀ
chloroꢀ2’ꢀmethoxyphenyl)ꢀ4ꢀchlorobenzenesulfonamide (10) (107 mg, 65%) as a white solid. Mp 142–
1
144 °C (lit.22 144–146 °C); H NMR (400 MHz, CDCl3) δ 3.66 (s, 3H), 6.67 (d, J = 8.7 Hz, 1H), 7.01
(dd, J = 8.7, 2.5 Hz, 1H), 7.03 (br s, 1H), 7.38–7.42 (m, 2H), 7.53 (d, J 2.5 Hz, 1H), 7.69–7.74 (m, 2H);
13C NMR (101 MHz, CDCl3) δ 56.0 (CH3), 111.5 (CH), 121.0 (CH), 125.3 (CH), 126.2 (C), 126.5 (C),
128.6 (2 × CH), 129.2 (2 × CH), 137.4 (C), 139.7 (C), 148.0 (C); MS (EI) m/z 331 (M+, 100), 296 (52),
262 (18), 158 (32), 156 (100), 126 (19), 111 (27), 93 (48), 75 (16).
N-(5’-Chloro-2’-methoxyphenyl)benzenesulfonamide (11).23 The reaction was performed as
described for 4ꢀchloroꢀNꢀ(5’ꢀchloroꢀ2’ꢀmethoxyphenyl)benzenesulfonamide (10) using 2ꢀbromoꢀ4ꢀ
chloroanisole (9) (221 mg, 1.00 mmol) and benzenesulfonamide (189 mg, 1.20 mmol). Purification by
flash column chromatography (petroleum ether/ethyl acetate, 7:3) gave Nꢀ(5’ꢀchloroꢀ2’ꢀ
methoxyphenyl)benzenesulfonamide (11) (199 mg, 67%) as a white solid. Mp 140–142 °C (lit.23 140–
142 °C); 1H NMR (400 MHz, CDCl3) δ 3.63 (s, 3H), 6.64 (d, J = 8.7 Hz, 1H), 6.98 (dd, J = 8.7, 2.6 Hz,
1H), 7.02 (br s, 1H), 7.40–7.47 (m, 2H), 7.50–7.53 (m, 1H), 7.55 (d, J = 2.6 Hz, 1H), 7.76–7.82 (m,
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2H); 13C NMR (101 MHz, CDCl3) δ 56.0 (CH3), 111.5 (CH), 120.8 (CH), 124.9 (CH), 126.1 (C), 126.9
(C), 127.2 (2 × CH), 128.9 (2 × CH), 133.1 (CH), 139.0 (C), 148.0 (C); MS (EI) m/z 297 (M+, 79), 156
(100), 93 (70), 77 (40), 51 (27).
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N-(5’-Chloro-2’-methoxyphenyl)-N-methylbenzenesulfonamide (12).23 To a solution of Nꢀ(5’ꢀ
chloroꢀ2’ꢀmethoxyphenyl)benzenesulfonamide (11) (38 mg, 0.13 mmol) in DMF (0.7 mL) was added
potassium carbonate (53 mg, 0.38 mmol) and iodomethane (24 ꢁL, 0.38 mmol). The reaction mixture
was stirred at room temperature for 2 h. The reaction mixture was then quenched with water (2 mL) and
extracted with diethyl ether (3 × 3 mL). The organic layers were combined, dried (MgSO4), filtered and
concentrated in vacuo. Purification by flash column chromatography (petroleum ether/ethyl acetate, 4:1)
gave Nꢀ(5’ꢀchloroꢀ2’ꢀmethoxyphenyl)ꢀNꢀmethylbenzenesulfonamide (12) (37 mg, 93%) as a colorless
oil. Spectroscopic data were consistent with the literature.23 1H NMR (500 MHz, CDCl3) δ 3.18 (s, 3H),
3.36 (s, 3H), 6.71 (d, J = 8.8 Hz, 1H), 7.23 (dd, J = 8.8, 2.7 Hz, 1H), 7.29 (d, J = 2.7 Hz, 1H), 7.44–7.50
(m, 2H), 7.53–7.59 (m, 1H), 7.66–7.71 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 37.8 (CH3), 55.3 (CH3),
112.6 (CH), 125.1 (C), 127.5 (2 × CH), 128.6 (2 × CH), 129.4 (CH), 129.9 (C), 131.8 (CH), 132.4 (CH),
139.2 (C), 155.2 (C); MS (EI) m/z 311 (M+, 41), 170 (100), 155 (39), 84 (15), 77 (19).
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2-(5-Acetylthien-2-yl)-4-chloroanisole (14). To a solution of 2ꢀbromoꢀ4ꢀchloroanisole (9) (160 mg,
0.730 mmol) in 1,4ꢀdioxane (8 mL) was added 5ꢀacetylthiopheneꢀ2ꢀboronic acid (148 mg, 0.870 mmol),
potassium carbonate (303 mg, 2.19 mmol) and water (6.0 mL). The reaction mixture was degassed with
argon for 0.1 h. Bis(triphenylphosphine)palladium(II) dichloride (51.0 mg, 0.0730 mmol) was added
and the reaction mixture was heated to 80 °C for 4 h. The reaction mixture was cooled to room
temperature and the organic solvent was removed under reduced pressure. The residue was dissolved in
ethyl acetate (15 mL), extracted with water (10 mL) and washed with brine (10 mL). The combined
organic layers were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash column
chromatography (petroleum ether/ethyl acetate, 19:1) gave 2ꢀ(5ꢀacetylthienꢀ2ꢀyl)ꢀ4ꢀchloroanisole (14)
(154 mg, 79%) as yellow solid. Mp 128–130 °C; IR 2941, 1653, 1436, 1277, 1259, 1021, 807, 677
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cm−1; H NMR (500 MHz, CDCl3) δ 2.57 (s, 3H), 3.95 (s, 3H), 6.93 (d, J = 8.8 Hz, 1H), 7.27 (dd, J =
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8.8, 2.6 Hz, 1H), 7.47 (d, J = 4.1 Hz, 1H), 7.64–7.67 (m, 2H); C NMR (126 MHz, CDCl3) δ 26.8
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(CH3), 55.9 (CH3), 112.9 (CH), 123.6 (C), 126.0 (C), 126.2 (CH), 128.0 (CH), 129.3 (CH), 132.1 (CH),
143.8 (C), 146.1 (C), 154.6 (C), 191.1 (C); MS (ESI) m/z 289 (MNa+, 100); HRMS (ESI) calcd for
C13H1135ClNaO2S (MNa+) 289.0060, found 289.0052.
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2-(5-Acetylthien-2-yl)-4-chlorophenol (3).5b 2ꢀ(5ꢀAcetylthienꢀ2ꢀyl)ꢀ4ꢀchloroanisole (14) (50.0 mg,
0.190 mmol) was dissolved in dichloromethane (3.0 mL) and cooled to −78 °C. Boron tribromide (1 M
in dichloromethane) (374 ꢁL, 0.370 mmol) was added dropwise and the reaction mixture was stirred at
−78 °C for 1 h, before warming to room temperature over 5 h. The reaction mixture was quenched by
the addition of a saturated solution of sodium bicarbonate (2 mL) and then extracted with
dichloromethane (4 × 3 mL). The organic layers were combined, dried (MgSO4), filtered and
concentrated in vacuo. Purification by flash column chromatography (petroleum ether/ethyl acetate, 4:1)
gave 2ꢀ(5ꢀacetylthienꢀ2ꢀyl)ꢀ4ꢀchlorophenol (3) (41.0 mg, 87%) as yellow solid. Mp 212–214 °C (lit.5b
218 °C); 1H NMR (500 MHz, DMSOꢀd6) δ 2.53 (s, 3H), 7.00 (d, J = 8.7 Hz, 1H), 7.25 (dd, J = 8.7, 2.6
Hz, 1H), 7.79 (d, J = 4.1 Hz, 1H), 7.84 (d, J = 2.6 Hz, 1H), 7.89 (d, J = 4.1 Hz, 1H), 11.00 (br s, 1H);
13C NMR (126 MHz, DMSOꢀd6) δ 27.0 (CH3), 118.5 (CH), 121.7 (C), 123.7 (C), 126.7 (CH), 127.3
(CH), 129.8 (CH), 133.8 (CH), 143.5 (C), 146.0 (C), 153.4 (C), 191.5 (C); MS (ESI) m/z 251 ([M−H]−,
100).
SUPPORTING INFORMATION AVAILABLE. 1H and 13C NMR spectra for all compounds. This
material is available free of charge via the Internet at http://pubs.acs.org.
ACKNOWLEDGEMENT. Financial support from the Ministry of Higher Education and Scientific
Research, Omar AlꢀMukhtar University, Libya (studentship to M.A.B.M.), EPSRC (EP/K503903/1) and
the University of Glasgow is gratefully acknowledged.
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(11) For some metalꢀfree examples of aryl chlorination, see: (a) Yadav, J. S.; Reddy, B. V. S.; Reddy,
P. S. R.; Basak, A. K.; Narsaiah, A. V. Adv. Synth. Catal. 2004, 346, 77. (b) Prakash, G. K. S.;
Mathew, T.; Hoole, D.; Esteves, P. M.; Wang, Q.; Rasul, G.; Olah, G. A. J. Am. Chem. Soc. 2004,
126, 15770. (c) Maddox, S. M.; Dinh, A. N.; Armenta, F.; Um, J.; Gustafson, J. L. Org. Lett.
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(12) For reviews, see: (a) Sheppard, T. D. Org. Biomol. Chem. 2009, 7, 1043. (b) Petrone, D. A.; Ye,
J.; Lautens, M. Chem. Rev. 2016, 116, 8003.
(13) For examples, see: (a) Tanemura, K.; Suzuki, T.; Nishida, Y.; Satsumabayashi, K.; Horaguchi,
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Chem. Int. Ed. 2010, 49, 2028. (c) Shen, X.; Hyde, A. M.; Buchwald, S. L. J. Am. Chem. Soc.
2010, 132, 14076. (d) Xu, J.; Zhu, X.; Zhou, G.; Ying, B.; Ye, P.; Su, L.; Shen, C.; Zhang, P. Org.
Biomol. Chem. 2016, 14, 3016.
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