Bronsted acidic ionic liquid accelerated halogenation of organic compounds with N-halosuccinimides (NXS)

Article abstract of DOI:10.3390/molecules18010074

The Bronsted-Acidic ionic liquid 1-methyl-3-(4-sulfobutyl) imidazolium triflate [BMIM(SO₃H)][OTf] was demonstrated to act efficiently as solvent and catalyst for the halogenation of activated organic compounds with N-halosuccinimides (NXS) under mild conditions with short reaction times. Methyl aryl ketones were converted into a-halo and a,a-dihaloketones, depending on the quantity of NXS used. Ketones with activated aromatic rings were selectively halogenated, however in some cases mixtures of a-halogenated ketone and ring-halogenated ketones were obtained. Activated aromatics were regioselectively ring halogenated to give mono- and dihalo-substituted products. The [BMIM(SO₃H)][OTf] ionic liquid (IL-A) was successfully reused eight times in a representative monohalogenation reaction with no noticeable decrease in efficiency. An effective halogenation scale-up in this IL is also presented. The reactivity trend and the observed chemo- and regioselectiivities point to an ET process in these IL-promoted halofunctionalization reactions.

Full text of DOI:10.3390/molecules18010074

Molecules 2013, 18, 74-96; doi:10.3390/molecules18010074
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Brønsted Acidic Ionic Liquid Accelerated Halogenation of
Organic Compounds with N-Halosuccinimides (NXS)
Dejan Vražič 1, Marjan Jereb 2, Kenneth K. Laali 3,* and Stojan Stavber 1,4,
*
1
Laboratory for Organic and Bioorganic Chemistry, Jožef Stefan Institute, Jamova 39,
1000 Ljubljana, Slovenia
2
3
4
Faculty for Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5,
1000 Ljubljana, Slovenia
Department of Chemistry, University North Florida, Science and Engineering Building,
1 UNF Drive, Jacksonville, FL 32224, USA
Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins CIPKeBiP,
Jamova 39, 1000 Ljubljana, Slovenia
* Author to whom correspondence should be addressed; E-Mail: stojan.stavber@ijs.si;
Fax: +386-1-423-54-00.
Received: 15 November 2012; in revised form: 6 December 2012 / Accepted: 11 December 2012 /
Published: 21 December 2012
Abstract: The Brønsted-acidic ionic liquid 1-methyl-3-(4-sulfobutyl)imidazolium triflate
[BMIM(SO3H)][OTf] was demonstrated to act efficiently as solvent and catalyst for the
halogenation of activated organic compounds with N-halosuccinimides (NXS) under mild
conditions with short reaction times. Methyl aryl ketones were converted into α-halo and
α,α-dihaloketones, depending on the quantity of NXS used. Ketones with activated
aromatic rings were selectively halogenated, however in some cases mixtures of
α-halogenated ketone and ring-halogenated ketones were obtained. Activated aromatics
were regioselectively ring halogenated to give mono- and dihalo-substituted products. The
[BMIM(SO3H)][OTf] ionic liquid (IL-A) was successfully reused eight times in a
representative monohalogenation reaction with no noticeable decrease in efficiency. An
effective halogenation scale-up in this IL is also presented. The reactivity trend and the
observed chemo- and regioselectiivities point to an ET process in these IL-promoted
halofunctionalization reactions.

Molecules 2013, 18
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Keywords: Brønsted-acidic ionic liquid; halogenation; aromatic ketones; NXS reagents;
green chemistry
1. Introduction
Halogenated organic compounds are highly versatile starting materials and intermediates in organic
and organometallic chemistry and their production has been under constant investigation. The topic
has been extensively reviewed [1–4]. Halogenation reactions are often associated with extensive waste
production and relatively high process costs. Increasing environmental and climate changes urge the
development of safer and “greener” synthetic pathways at reduced costs. The main reaction waste is
usually the organic solvent used as reaction medium; moreover volatile organics have severe
environmental and health issues.
N-halosuccinimides are very popular as halogen-transfer reagents [5–9]; however they are usually
not reactive enough for direct halogenation and require a Lewis acid or a Brønsted acid catalyst. The
catalysts employed are usually moisture sensitive, they are often metallic or strongly acidic, produce
toxic waste, and are costly.
Halogenation of aromatic compounds in different ILs has been recently reviewed [10,11] and
further studied [12]. Fluorination of arenes with F-TEDA-BF4 was examined in imidazolium-ILs [13].
Other earlier studies include chlorination of aromatics with trichloroisocyanuric acid in IL-A
(Figure 1) [14], oxidative chlorination with HCl in [Hmim][NO3] [15], bromination of aromatics in
tribromide-based ILs [16–19], iodination with I2/H2O2 in BMIM-IL [20], I2/F-TEDA-BF4 in
imidazolium- and pyridinium-IL, also with I2 or MeI/Koser’s reagent in BMIM-IL [21], iodination of
alcohols in [Hmim][HSO4] [22], and with N-iodosaccharin [23].
Brønsted-acidic ionic liquids such as [BMIM(SO3H)][OTf] [24] (IL-A) have attracted considerable
attention as dual solvent/catalysts and were employed in diverse acid-catalyzed transformations [25–30].
Figure 1. Structure of investigated imidazolium-based ionic liquids IL-A and IL-B.
In continuation of our previous studies on application of ionic liquids as solvents and catalysts in
synthesis [31–43], we report on the utility of IL-A for halofunctionalization of organic molecules with
NXS reagents.
2. Results and Discussion
Halogenation of acetophenone (1) with NIS, NBS and NCS was studied in IL-A and IL-B (Figure 1),
and α-halogenation took place with all three reagents (Table 1). Iodination of 1 with 1.1 equiv. of NIS

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76
at 55 °C gave 2a with significantly higher conversion in IL-A than in IL-B; albeit with slightly lower
selectivity (Table 1, entries 1 and 2). Similar results were obtained in bromination with NBS (entries 3
and 4). Bromination with 2.2 equiv. of NBS in IL-A resulted in quantitative dibromination, whereas in
IL-B only monobromination took place (entries 5 and 6). Chlorofunctionalization with 1.1 equivalents
of NCS in the both IL-A and IL-B gave 2c as the main product; whereas regioselectivity in IL-A
changed after prolonged heating and 3c was obtained as the mayor product (entries 7–9). Reaction
with 2.2 equiv. of NCS in IL-B gave 2c as major and 3c as minor products, whereas 3c was formed
exclusively in IL-A (entries 10 and 11). The results confirm the superior catalytic effect of the
Brønsted acidic IL-A.
Table 1. Halogenation of acetophenone 1 with N-halosuccinimides (NXS) in 1-butyl-3-
methylimidazolium based ionic liquids a.
NXS
(equiv.)
1.1
Reaction
Conversion
Entry
X
IL
T (°C)
2 / 3
time (min)
of 1 b (%)
1
2
I
IL-B
IL-A
IL-B
IL-A
IL-B
IL-A
IL-B
IL-A
IL-A
IL-B
IL-A
55
55
55
55
70
70
70
70
70
70
70
10
10
20
20
30
30
30
30
90
30
30
13
98
22
95
60
100
97
47
63
92
100 / 0
93 / 7
I
1.1
3
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
1.1
100 / 0
86 / 14
100 / 0
0 / 100
85 / 15
90 / 10
15 / 85
91 / 9
4
1.1
5
2.2
6
2.2
7
1.1
8
1.1
9
1.1
10
11
2.2
2.2
100
0 / 100
a
b
Reaction conditions: 1 mmol of 1, 1.1 or 2.2 mmol of NXS stirred in 3 mmol of IL; Conversion
determined by 1H-NMR.
Focusing on the effect of the structure of aryl methyl ketones 4 on halogenation with
N-halosuccinimides in IL-A (Table 2), compound 4a was selectively converted into its α-iodo
derivative 5a (entry 1). Functionalization of 4a with 1.1 equiv. of NBS was less selective, furnishing
α-bromo- and α,α-dibromo- substituted ketones 6a and 7a (entry 2), while reaction with 2.2 equiv of
NBS yielded 7a in excellent yield (entry 3). Chlorination with 2.2 equiv. of NCS selectively produced
the α,α-dichloroketone 8a (entry 4).
Halogenation of 2-acetylthiophene (4b) yielded the α-iodoketone 5b regioselectively (entry 5).
Reaction of 4b with NBS (1.1 equiv.) exhibited a similar level of selectivity as with 4a, forming the
mono- and dibrominated products 6b and 7b (entry 6), and with 2.2 equiv. of NBS 7b in high yield.
Functionalization with 2.2 equiv. of NCS selectively furnished the -dichloroketone 8b (entry 8).
Compound 4c was regioselectively converted to its α-iodoketone 5c with NIS in high yield (entry 9).
Bromination with NBS was somewhat less selective than in the previous cases giving a mixture of

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α-bromo and α,α-dibromoketones 6c and 7c (entry 10), while with 2.2 equiv. of NBS 7c was
selectively obtained in high yield (entry 11). The reaction temperatures were in 55–70 °C range,
depending on the reactivity of the NXS reagent, and the reaction times varied from 10 to 150 minutes.
It is noteworthy that no ring functionalization products were formed with ketones 4a, 4b and 4c,
despite the additional activation of the aromatic ring with an EDG functionalization, which was
obviously not enough for acetyl group deactivation of the aromatic part of the target.
Table 2. The effect of aryl methyl ketone 4 structure on halofunctionalization with
N-halosuccinimides (NXS) in [BMIM(SO3H)][OTf] (IL-A) a.
O
5: X = I
X
6: X = Br
Ar
O
5-6
NXS,
IL-A,
Ar
Me
O
4
X
7: X = Br
8: X = Cl
Ar
X
7-8
Reaction conditionsa
Yield (%) b
Entry
Ar
Products
NXS (mmol) / T (°C) / t (min)
NIS (1.1) / 55 / 10
NBS (1.1) / 55 / 20
NBS (2.2) / 70 / 60
NCS (2.2) / 70 / 150
NIS (1.1) / 55 / 10
NBS (1.1) / 55 / 10
NBS (2.2) / 70 / 30
NCS (2.2) / 70 / 60
NIS (1.1) / 55 / 10
NBS (1.1) / 55 / 20
NBS (2.2) / 70 / 30
5 or 6
7 or 8
1
5a
94 (84)
72 (66)
2
6a / 7a
7a
19 (18)
96 (94)
97 (86)
4a
3
4
8a
5
5b
91 (80)
75 (72)
6
6b / 7b
7b
16 (15)
95 (85)
96 (67)
7
8
8b
9
5c
92 (80)
71 (62)
10
11
6c / 7c
22 (20)
7c
100 (91)
a Reaction conditions: 1 mmol of 4, 1.1 or 2.2 mmol of NXS stirred in 3 mmol of IL-A at 55–70 °C for 10 to
b
1
150 min; Relative yields determined by H-NMR, values in the brackets refer to the yields of isolated
pure products.
Halofunctionalization of 4c with excess of NCS was studied in IL-A at 70 °C (Scheme 1). With 2.2
equiv. of NCS a mixture of 2,2-dichloro-1-(p-anisyl)ethanone (8c) and 2,2-dichloro-1-(3-chloro-4-
methoxyphenyl)ethanone (9) was obtained in 58:42 ratio, respectively, and with 3.3 equiv. of NCS
selectively compound 9 was formed in high yield as the sole product.

Molecules 2013, 18
Scheme 1. Chlorination of 4′-methoxyacetophenone (4c) with NCS.
78
2.2 equiv. NCS,
90 min
58
/
42
O
O
O
IL-A (3 mmol),
70 °C
CHCl2
CHCl2
+
Me
MeO
MeO
9
8c
MeO
Cl
4c
3.3 equiv. NCS,
180 min
0
/
100
Yield = 76%
In the next phase of this study halofunctionalization of isomeric dimethoxyacetophenones 10, 14,
18 and trimethoxyacetophenone 25 were examined (Schemes 2–4). Transformation of 10 with
1.1 equiv. of NBS furnished a mixture of α-bromoketone 12 and α,α-dibromo derivative 13, whereas
with 2.2 equivalents of NBS, 13 was obtained as a sole product in high yield. Compound 10 was
regioselectively converted into the α-iodoketone 11 with 1.1 equiv. NIS in good yield (Scheme 2).
Scheme 2. Halofunctionalization of 3′,4′-dimethoxyacetophenone (10) and 2′,4′-
dimethoxyacetophenone (14) with NXS reagents in [BMIM(SO3H)][OTf] (IL-A) medium a.
a
Reaction conditions: 1 mmol of ketone, NXS (1.1 or 2.2 mmol) stirred in 3 mmol of IL-A at 55 °C for
10–60 min. Relative yields determined by 1H-NMR. Values in brackets refer to the yields of isolated pure products.
Isomeric 2′,4′-dimethoxyacetophenone (14) exhibited different selectivity in reaction with 1.1
equiv. of NIS, forming a mixture of the α-iodoketone 15 as the major product along with 1-acetyl-5-
iodo-2,4-dimethoxybenzene (16) and 2-iodo-1-(5-iodo-2,4-dimethoxyphenyl)ethanone (17) as minor
products (Scheme 2). 2′,6′-Dimethoxyacetophenone (18) exhibited a similar reactivity trend as 14.
Functionalization of 18 with 4.4 equiv. of NCS in IL-A selectively furnished 2,2-dichloro-1-(3,5-
dichloro-2,6-dimethoxyphenyl)ethanone (21) in a good yield (Scheme 3). Reaction of 18 with 1.1

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79
equiv. of NIS furnished a mixture of α-iodoketone 19 as major, and 2-iodo-1-(3-iodo-2,6-
dimethoxyphenyl)ethanone (20) as minor product. Functionalization of 18 with 1.1 equiv. of NBS
yielded the 3-bromo derivative 22 (as the main product), along with 2-bromo-1-(3-bromo-2,6-
dimethoxyphenyl)ethanone (23) and 2,2-dibromo-1-(3,5-dibromo-2,6-dimethoxyphenyl)ethanone (24)
as minor products. A similar reactivity trend was observed with 2.2 equiv. of NBS, forming 22 and 24
(but 23 was not formed). When 4.4 equiv. of NBS was employed, the tetrabromo-derivative 24 was
isolated as the sole product in good yield.
Scheme 3. Halofunctionalization of 2′,6′-dimethoxyacetophenone (18) with NXS reagents
in [BMIM(SO3H)][OTf] (IL-A) medium a.
a Reaction conditions: 1 mmol of 18, NXS (1.1, 2.2 or 4.4 mmol) stirred in 3 mmol of IL-A at 55, 70 or 85 °C
1
for 0.17–18 h. Relative yields determined by H-NMR. Values in brackets refer to the yields of isolated
pure products.
2′,3′,4′-Trimethoxyacetophenone (25) was rapidly (within minutes) converted to the α-iodo
derivative 26 with 1.1 equiv. of NIS (Scheme 4). Reaction of 25 with NBS gave a mixture of up to four
compounds, depending on the quantity of the NBS. With 1.1 equiv. of NBS the α-bromoketone 27 was
the main product, and α,α-dibromoketone 28, 2-bromo-1-(5-bromo-2,3,4-trimethoxyphenyl)ethanone
(29) and tribromo-substituted ketone 30 were the minor products. With 2.2 equiv. of NBS 29 and 30
were the only isolated products (27 and 28 were not observed). Reaction of 25 with 3.3 equiv. of NBS
exclusively yielded 30 in excellent yield (see Scheme 4).
To explore the potential utility of NXS/IL-A system in ring halogenation of activated arenes,
halofunctionalization of anisole (31), 1,3-dimethoxybenzene (34), toluene (37), and 2-methylthiophene
(40) were examined (Scheme 5).
Reaction of anisole (31) with 1.1 equiv. of NXS was highly para-selective, forming the
corresponding iodo- 32a, bromo- 32b and chloro-derivative 32c (in 84-78% isolated yields) with no
ortho-substitution being observed. Reaction of 31 with 2.2 equiv. of NXS selectively produced
2,4-dihaloanisoles 33a–c in high yields.

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Scheme 4. Halofunctionalization of 2′,3′,4′-trimethoxyacetophenone (25) with NXS
reagents in [BMIM(SO3H)][OTf] (IL-A) medium a.
a Reaction conditions: 1 mmol of 25, NXS (1.1, 2.2 or 3.3 mmol) stirred in 3 mmol of IL A at 55 or 70 °C for
1
10–120 min. Relative yields determined by H-NMR. Values in brackets refer to the yields of isolated
pure products.
Scheme 5. Transformation of activated aromatic molecules with N-halosuccinimides
(NXS) in [BMIM(SO3H)][OTf] (IL-A) a.
a
Reaction conditions: 1 mmol of substrate, NXS (1.1, 2.2 or 3.3 mmol) stirred in 3 mmol of IL A at 55 or
70 °C for 0.17–3 h. Relative yields determined by 1H-NMR. Values in brackets refer to the yields of isolated
pure products.

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1,3-Dimethoxybenzene (34) was transformed with 2.2 equiv. of NIS, NBS and NCS into 2,4-dihalo-
1,5-dimethoxybenzenes 35a–c in high yields. Transformation of 34 with 3.3 equiv. of NCS led to a
dearomatization of the target molecule and the formation of 2,4,4-trichloro-5-methoxycyclohexa-2,5-
dienone (36) in 84% yield. This compound is the result of chlorination of aromatic ring resulting
primarily in 35c and further regioselective 1,4-addition-elimination process following ipso-
chlorination and demethylation of the para-methoxy group, what was confirmed by an independent
experiment and the structure of 36 unequivocally distinguished from the possibly formed isomeric
4,6,6-trichloro-3-methoxycyclohexa-2,4-dienone using 2D-NMR measurement techniques HSQC and
HMBC (Figure 2). The also expected 1,3,5-trichloro-2,4-dimethoxybenzene was not formed probably
because of substantial sterical hindrance between the two methoxy substituents on the aromatic ring.
Figure 2. Copies of 2D-NMR spectra for 2,4,4-trichloro-5-methoxycyclohexa-2,5-dienone (36).
H 3
HSQC
H 1
H 2
ppm
0
20
40
C 7
60
80
O
100
120
140
C 2
Cl
C1
H1
O
C6
C5
C2
C3
H3
C7 H3
H3
H2
C4
C 5
Cl
Cl
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
H 3
3.5
3.0
2.5
2.0
ppm
HMBC
H 2
H 1
ppm
0
20
40
C 7
60
C 4
O
80
Cl
H2
C1
H1
O
100
120
140
160
180
200
ppm
C6
C2
C3
H3
C 2
C5
C7 H3
C4
C 6
H3
C 5
Cl
Cl
C 3
C 1
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
Halogenation of toluene (37) with 1.1 equiv. of NXS gave 4- and 2-halotoluene. The ortho/para
ratio with NIS was 42:58, whereas with NBS and NCS this ratio changed in favor of the ortho-isomer.
A similar regioselectivity was reported in halogenation of toluene with NBS and NCS in the presence of
FeCl3 [5].

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2-Methylthiophene (40) was selectively converted into its 5-iodo derivative 41 in high yield with
1.1 equiv. of NIS. Reaction of 40 with NCS and NBS were also carried out successfully, however the
isolated yields were low due to the volatility of the products.
Having discovered these highly efficient halofunctionalization reactions we then explored the
possibility to make the process more economical through recycling and reuse of the IL. To explore this
possibility, halogenation of acetophenone (1) with 1.1 equiv. of NIS was selected as a prototype
reaction and the reaction was successfully repeated in reused/recycled IL-A for 8 cycles (Table 3) with
no notable decrease in the conversions. To address the question of relative reactivity of the NXS
reagent versus recycling and reuse, bromofunctionalization of 1 with 2.2 equivalents of NBS was
examined (Table 3) over 5 repeated cycles, showing a gradual decrease in the dibromo derivative 3b
with concomitant increase in monobromo product 2b. The data underscores the importance of IL-A as
a promoter in these halogen-transfer reactions.
Table 3. The effect of [BMIM(SO3H)][OTf] (IL-A) recycling on transformation of
acetophenone 1 with NXS reagents.
O
O
1.1 mmol NIS, IL-A (3 mmol),
55 °C, 10 min
Me
Ph
CH2I
Ph
1
2a
Repetition number
Yield (%)
1
2
3
4
5
6
7
8
86
90
90
88
90
89
87
92
Repetition number
Product distribution (2b:3b)
1
2
3
4
5
0:100
4:96
12:88
25:75
33:67
Finally to explore the feasibility to perform these reactions on larger scales than reported thus far,
bromination of 1 was carried out on a 9 mmol scale (a 9 fold increase), by using 19.8 mmols of NBS,

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and 27 mmol of IL-A. The 2,2-dibromo-1-phenylethanone 3b was obtained in 90% isolated yield after
40 minutes at 70 °C.
Concerning a plausible mechanism for halofunctionalization with NXS/[BMIM(SO3H)][OTf]
systems, previous studies [44–47] have shown that ring halogenations of activated aromatics with NIS,
NBS and NCS proceed through an electron transfer (ET) pathway as the main reaction channel. Based
on the fact that in the present study under the reaction conditions employed only activated aromatics
could be halogenated, and considering the observed chemo- and regioselectivity patterns, in all
probability the ET reaction pathway is also most likely operating in these reactions. The role of acidic IL
as a catalyst is to enhance the electrophilic character of NXS reagents by additional polarization of N-X
bond. In halogenation of phenyl methyl ketones the acidic IL could also act as enolization catalyst,
accelerating electrophilic addition of halogen. With the studied ketones, side chain halogenation is
the primary event with ring halogenation manifesting only when the ring is highly activated
(two methoxy groups).
3. Experimental
3.1. General
All chemicals were purchased from commercial sources and used without further purification.
Column chromatography was carried out using silica gel 60 (particle size: 0.063–0.2 mm) and
preparative thin layer chromatography using PLC Silica gel 60 F254, 2 mm plates. Melting points were
obtained with a Büchi 535 apparatus. For obtaining IR spectra on FTS3000-MX spectrometer, either a
KBr pellet of the product was made or NaCl plates were used based on the physical state of product.
NMR spectra were recorded on a Bruker Avance 300 DPX instrument (1H: 300 MHz, 13C: 75.5 MHz).
1
1
The H spectra were referred to an internal standard (0 ppm for TMS) or to the residual H signal of
CHCl3 at 7.26 ppm and for CD3COCD3 at 2.05 ppm (central line). The 13C spectra were referred to the
residual signal of CDCl3 (77.0 ppm, central line) or CD3COCD3 (30.8 ppm, central line). Elemental
analysis was performed on a Perkin-Elmer 2400-Series 2 apparatus.
3.2. Representative Procedure for Halogenation of Aromatic Compounds
To a stirred mixture of the aromatic compound (1 mmol) in ionic liquid (3 mmol), N-halo-
succinimide (1.1–4.4 mmol) was added. The reaction mixture was stirred at 55, 70 or 85 °C until
completion (monitored by TLC). The mixture was cooled to room temperature and washed three times
with dichloromethane. The combined organic fractions were washed with aqueous Na2S2O3 and
NaHCO3, dried over anhydrous Na2SO4 and filtered. Solvent was removed under reduced pressure and
the crude reaction mixture was analyzed by 1H-NMR. Isolation of products from reaction mixtures was
accomplished by preparative TLC or column chromatography and pure compounds were analyzed by
NMR, MS and IR spectroscopy. Data for known compounds were verified from the literature while the
new compounds were completely verified by spectroscopic data and C, H, N elemental analysis.
2-Iodo-1-phenylethanone (2a). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NIS, r.t. = 10 min, 55 °C,
preparative chromatography SiO2, hexane/CH2Cl2 = 2.5/7.5, orange oil (86%), mp: lit [48] 33–35 °C;

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1H-NMR (CDCl3): δ 8.03–7.97 (m, 2H), 7.64–7.57 (m, 1H), 7.54–7.45 (m, 2H), 4.37 (s, 2H);
IR(NaCl): 3059, 2976, 2938, 1674, 1595, 1449, 1418, 1271, 1173, 1105, 1001, 791, 747, 703 cm−1; MS
(ESI): 247.0 (M+H)+.
2-Bromo-1-phenylethanone (2b). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NBS, r.t. = 20 min, 55
°C), preparative chromatography, SiO2, hexane/CH2Cl2 = 2.5/7.5, white solid (73%), mp: 46.8–48.2 °C
1
(lit [49] 48.8–49.3 °C); H-NMR (CDCl3): δ 8.02–7.97 (m, 2H), 7.66–7.57 (m, 1H), 7.55–7.45 (m,
2H), 4.46 (s, 2H); IR (KBr): 3058, 3002, 2951, 1694, 1593, 1447, 1390, 1281, 1198, 991, 881, 746,
685, 623 cm−1; MS (ESI): 199.0 (M+H)+, 201.0 (M+2+H)+.
2-Chloro-1-phenylethanone (2c). One mmol of substrate, 3 mmol IL-B, 1.1 mmol NCS, r.t. = 30 min,
70 °C, preparative chromatography SiO2, hexane/CH2Cl2 = 2.5/7.5, white solid (74%), mp:
1
53.2–54.2 °C (lit [50] 55 °C); H-NMR (CDCl3): δ 8.00–7.93 (m, 2H), 7.66–7.58 (m, 1H), 7.55–7.46
(m, 2H), 4.71 (s, 2H); IR (neat): 2951, 1692, 1595, 1580, 1448, 1397, 1209, 999, 769, 746, 685, 640
cm−1; MS (ESI): 155.0 (M+H)+, 157.0 (M+2+H)+.
2,2-Dibromo-1-phenylethanone (3b). One mmol of substrate, 3 mmol IL-A, 2.2 mmol NBS, r.t. = 30 min,
1
70 °C, CC SiO2, CH2Cl2, white solid (82%), mp: 31.5–32.9 °C (lit [51] 33.5–34.5 °C); H-NMR
(CDCl3): δ 8.13–8.04 (m, 2H), 7.69–7.60 (m, 1H), 7.57–7.46 (m, 2H), 6.70 (s, 1H); IR (KBr): 1693,
1587, 1445, 1267, 1198, 983, 797, 705, 678, 625 cm−1; MS (ESI): 276.9 (M+H)+, 278.9 (M+2+H)+,
280.9 (M+4+H)+.
2,2-Dichloro-1-phenylethanone (3c). One mmol of substrate, 3 mmol IL-A, 2.2 mmol NCS, r.t. = 120 min,
1
70 °C, CC SiO2, CH2Cl2, yellow oil [52] (96%); H-NMR (CDCl3): δ 8.13–8.06 (m, 2H), 7.69–7.62
(m, 1H), 7.57–7.49 (m, 2H), 6.68 (s, 1H); IR (NaCl): 3065, 3008, 1705, 1595, 1449, 1278, 1222, 1182,
990, 932, 810, 774, 685, 654 cm−1; MS (ESI): 154.0 (M−Cl+H)+, 156.0 (M−Cl+2+H)+.
2-Iodo-1-(2-naphthyl)ethanone (5a). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NIS, r.t. = 10 min,
55 °C, preparative chromatography SiO2, hexane/CH2Cl2 = 2.5/7.5, yellow solid (84%), mp: 87.5–90.2 °C
1
(lit [53] 87–87.5 °C); H-NMR (CDCl3): δ 8.54–8.51 (m, 1H), 8.06–7.96 (m, 2H), 7.94–7.87 (m, 2H),
7.67–7.54 (m, 2H), 4.49 (s, 2H); IR(KBr): 1661, 1622, 1464, 1368, 1285, 1231, 1144, 1123, 1094,
1020, 991, 866, 804, 750 cm−1; MS (ESI): 297.0 (M+H)+.
2-Iodo-1-(2-thienyl)ethanone (5b). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NIS, r.t. = 10 min,
1
55 °C, preparative chromatography SiO2, hexane/CH2Cl2 = 2.5/7.5, yellow oil [54] (80%); H-NMR
(CDCl3): δ 7.80 (dd, J = 3.9 Hz, J = 1.0 Hz, 1H), 7.69 (dd, J = 4.9 Hz, J = 1.0 Hz, 1H), 7.16 (dd,
J = 4.9 Hz, J = 3.9 Hz, 1H), 4.30 (s, 2H); IR (NaCl): 3089, 3036, 2972, 2936, 1650, 1514, 1412, 1355,
1280, 1164, 1099, 1061, 963, 858, 727 cm−1; MS (ESI): 252.9 (M+H)+.
1-(p-Anisyl)-2-iodoethanone (5c). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NIS, r.t. = 10 min,
55 °C, preparative chromatography SiO2, hexane/CH2Cl2 = 2.5/7.5, grey solid (80%), mp: 56.3–59.4 °C
1
(lit [48] 57–59.5 °C); H-NMR (CDCl3): δ 7.97 (d, J = 8.9 Hz, 2H), 6.95 (d, J = 8.9 Hz, 2H), 4.31
(s, 2H), 3.89 (s, 3H); IR (KBr): 3032, 2972, 1656, 1601, 1568, 1508, 1454, 1422, 1288, 1257, 1173,
1099, 1016, 1001, 845, 754 cm−1; MS (ESI): 277.0 (M+H)+.

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2-Bromo-1-(2-naphthyl)ethanone (6a). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NBS, r.t. = 20 min,
55 °C, preparative chromatography SiO2, hexane/CH2Cl2 = 2.5/7.5, grey solid (66%), mp: 80.3–82.2 °C
1
(lit [55] 78–79.5 °C); H-NMR (CDCl3): δ 8.54–8.50 (m, 1H), 8.07–7.96 (m, 2H), 7.96–7.87 (m, 2H),
7.68–7.54 (m, 2H), 4.58 (s, 2H); IR (KBr): 2999, 2948, 1690, 1624, 1591, 1468, 1385, 1175, 1159,
1127, 1028, 853, 812, 740, 680 cm−1; MS (ESI): 249.0 (M+H)+, 251.0 (M+2+H)+.
2-Bromo-1-(2-thienyl)ethanone (6b). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NBS, r.t. = 10 min,
55 °C, preparative chromatography SiO2, hexane/CH2Cl2 = 2.5/7.5, yellow oil (72%), mp: lit [56]
31–33 °C; 1H-NMR (CDCl3): δ 7.81 (dd, J = 3.9 Hz, J = 1.0 Hz, 1H), 7.72 (dd, J = 4.9 Hz, J = 1.0 Hz,
1H), 7.17 (dd, J = 4.9 Hz, J = 3.9 Hz, 1H), 4.36 (s, 2H); IR (NaCl): 3098, 2942, 1652, 1514, 1412, 1355,
1287, 1194, 1110, 1061, 973, 939, 854, 727, 667 cm−1; MS (ESI): 204.9 (M+H)+, 206.9 (M+2+H)+.
2-Bromo-1-(p-anisyl)ethanone (6c). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NBS, r.t. = 20 min,
55 °C, preparative chromatography SiO2, hexane/CH2Cl2 = 2.5/7.5, pale red (62%), mp: 68.4–69.7 °C
1
(lit [56] 69–71 °C); H-NMR (CDCl3): δ 7.97 (d, J = 8.9 Hz, 2H), 6.96 (d, J = 8.9 Hz, 2H), 4.40
(s, 2H), 3.89 (s, 3H); IR (KBr): 2938, 1688, 1597, 1510, 1326, 1263, 1208, 1167, 1115, 1016, 986,
745, 685 cm−1; MS (ESI): 229.0 (M+H)+, 231.0 (M+2+H)+.
2,2-Dibromo-1-(2-naphthyl)ethanone (7a). One mmol of substrate, 3 mmol IL-A, 2.2 mmol NBS,
r.t. = 60 min, 70 °C, CC SiO2, CH2Cl2, white solid (94%), mp: 78.1–80.7 °C (lit [57] 100–101.5 °C);
1H-NMR (CDCl3): δ 8.67–8.63 (m, 1H), 8.13–8.07 (m, 1H), 8.04–7.87 (m, 3H), 7.70–7.56 (m, 2H),
6.86 (s, 1H); IR (KBr): 1682, 1620, 1587, 1358, 1273, 1182, 1153, 1119, 820, 733, 683, 623 cm−1; MS
(ESI): 326.9 (M+H)+, 328.9 (M+2+H)+, 330.9 (M+4+H)+.
2,2-Dibromo-1-(2-thienyl)ethanone (7b). One mmol of substrate, 3 mmol IL-A, 2.2 mmol NBS, r.t. = 30 min,
1
70 °C, preparative chromatography SiO2, hexane/CH2Cl2 = 2.5/7.5, orange oil [58] (85%); H-NMR
(CDCl3): δ 8.03–7.98 (m, 1H), 7.80–7.76 (m, 1H), 7.22–7.18 (m, 1H), 6.48 (s, 1H); IR (NaCl): 3098,
3013, 1669, 1512, 1411, 1354, 1279, 1179, 1065, 937, 858, 726, 665, 638 cm−1; MS (ESI): 282.9
(M+H)+, 284.9 (M+2+H)+, 286.8 (M+4+H)+.
2,2-Dibromo-1-(p-anisyl)ethanone (7c). One mmol of substrate, 3 mmol IL-A, 2.2 mmol NBS,
r.t. = 30 min, 70 °C, CC SiO2, CH2Cl2, white solid (91%), mp: 86.7–88.9 °C (lit [51] 93–94 °C);
1H-NMR (CDCl3): δ 8.08 (d, J = 9.0 Hz, 2H), 6.98 (d, J = 9.0 Hz, 2H), 6.66 (s, 1H), 3.90 (s, 3H);
IR(KBr): 3032, 1674, 1597, 1566, 1504, 1420, 1314, 1263, 1202, 1177, 1146, 1020, 982, 845, 810,
761, 706, 683 cm−1; MS (ESI): 306.9 (M+H)+, 308.9 (M+2+H)+, 310.9 (M+4+H)+.
2,2-Dichloro-1-(2-naphthyl)ethanone (8a). One mmol of substrate, 3 mmol IL-A, 2.2 mmol NCS,
r.t. = 150 min, 70 °C, CC SiO2, CH2Cl2, yellow solid (86%), mp: 66.6–69.8 °C (lit [59] 80–80.5 °C);
1H-NMR (CDCl3): δ 8.68–8.62 (m, 1H), 8.13–8.06 (m, 1H), 8.04–7.87 (m, 3H), 7.71–7.56 (m, 2H),
6.83 (s, 1H); IR (KBr): 3059, 1699, 1626, 1596, 1466, 1357, 1282, 1219, 1175, 1125, 866, 824, 785, 742,
657 cm−1; MS (ESI): 239.0 (M+H)+, 241.0 (M+2+H)+.
2,2-Dichloro-1-(2-thienyl)ethanone (8b). One mmol of substrate, 3 mmol IL-A, 2.2 mmol NCS,
r.t. = 90 min, 70 °C, preparative chromatography SiO2, hexane/CH2Cl2 = 3.5/6.5, orange oil [60]

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1
(67%); H-NMR (CDCl3): δ 8.02 (dd, J = 3.9 Hz, J = 1.0 Hz, 1H), 7.80 (dd, J = 4.9 Hz, J = 1.0 Hz,
1H), 7.21 (dd, J = 4.9 Hz, J = 3.9 Hz, 1H), 6.47 (s, 3H); IR (NaCl): 3100, 3007, 1682, 1512, 1409,
1356, 1277, 1240, 1217, 1188, 1067, 944, 858, 802, 720, 668 cm−1; MS (ESI): 194.9 (M+H)+.
2,2-Dichloro-1-(p-anisyl)ethanone (8c). One mmol of substrate, 3 mmol IL-A, 2.2 mmol NCS,
r.t. = 90 min, 70 °C, preparative chromatography SiO2, hexane/CH2Cl2 = 3.5/6.5, white solid (36%),
1
mp: 76.9–78.2 °C (lit [61] 78–79 °C); H-NMR (CDCl3): δ 8.08 (d, J = 8.9 Hz, 2H), 6.99 (d,
J = 8.9 Hz, 2H), 6.63 (s, 1H), 3.90 (s, 3H); IR (KBr): 3028, 1683, 1600, 1568, 1506, 1422, 1318, 1298,
1265, 1236, 1175, 1024, 847, 795, 745, 646 cm−1; MS (ESI): 219.0 (M+H)+, 221 (M+2+H)+.
2,2-Dichloro-1-(3-chloro-4-methoxyphenyl)ethanone (9). One mmol of substrate, 3 mmol IL-A,
3.3 mmol NCS, r.t. = 180 min, 70 °C; preparative chromatography SiO2, hexane/CH2Cl2 = 2.5/7.5;
white solid (76%); mp: 99.3–100.9 °C ; 1H-NMR (CDCl3): δ 8.14 (d, J = 2.3 Hz, 1H), 8.05 (dd, J = 8.8 Hz,
J = 2.3 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 6.57 (s, 1H), 4.00 (s, 3H); 13C-NMR (CD3COCD3): δ 185.7,
161.9, 133.1, 132.5, 127.0, 124.6, 114.3, 70.0, 58.2; IR (KBr): 2982, 1686, 1591, 1508, 1318, 1281,
1227, 1182, 1148, 1065, 1009, 824, 797, 750, 700, 631 cm−1; MS (ESI): 253.0 (M+H)+, 255.0
(M+2+H)+; HRMS: calcd for C9H8Cl3O2: 252.9590; found: 252.9601; Anal. Calcd for C9H7Cl3O2:
C, 42.64; H, 2.78. Found: C, 42.92; H, 2.72.
2-Iodo-1-(3,4-dimethoxyphenyl)ethanone (11). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NIS,
r.t. = 15 min, 55 °C, preparative chromatography SiO2, CH2Cl2, yellow solid (69%), mp: 62.0–65.0 °C
(lit [62] 65.2–66.2 °C); 1H-NMR (CDCl3): δ 7.62 (dd, J = 8.4 Hz, J = 2.0 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H),
6.90 (d, J = 8.4 Hz, 1H), 4.33 (s, 2H), 3.97 (s, 3H), 3.95 (s, 3H); IR (KBr): 2934, 2837, 1652, 1583, 1514,
1451, 1425, 1273, 1231, 1154, 1095, 1019, 877, 810, 768, 748, 617 cm−1; MS (ESI): 307.0 (M+H)+.
2-Bromo-1-(3,4-dimethoxyphenyl)ethanone (12). One mmol of substrate, 3 mmol IL-A, 1.1 mmol
NBS, r.t. = 60 min, 55 °C, preparative chromatography SiO2, CH2Cl2, white solid (63%), mp:
80.5–81.6 °C (lit [63] 80–81 °C); 1H-NMR (CDCl3): δ 7.62 (dd, J = 8.4 Hz, J = 1.9 Hz, 1H), 7.55 (d,
J = 1.9 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 4.41 (s, 2H), 3.97 (s, 3H), 3.95 (s, 3H); IR (KBr): 2966,
2940, 2843, 1682, 1586, 1515, 1466, 1420, 1283, 1244, 1155, 1020, 868, 798, 769, 683, 619 cm−1; MS
(ESI): 259.0 (M+H)+, 261.0 (M+2+H)+.
2,2-Dibromo-1-(3,4-dimethoxyphenyl)ethanone (13). One mmol of substrate, 3 mmol IL-A, 2.2 mmol
NBS, r.t. = 120 min, 70 °C; column chromatography SiO2, CH2Cl2; white solid (87%); mp: 79.0–81.7 °C;
1H-NMR (CDCl3): δ 7.74 (dd, J = 8.4 Hz, J = 2.0 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 6.92 (d,
J = 8.4 Hz, 1H), 6.69 (s, 1H), 3.98 (s, 3H), 3.95 (s, 3H); 13C-NMR (CD3COCD3): 186.8, 156.9, 151.6,
126.2, 125.4, 113.7, 112.8, 57.4, 57.3, 43.3; IR (KBr): 3017, 2967, 2933, 2837, 1676, 1587, 1518,
1454, 1416, 1350, 1279, 1238, 1190, 1155, 1016, 881, 800, 756, 689, 621 cm−1; MS (ESI): 336.9
(M+H)+, 338.9 (M+2+H)+, 340.9 (M+4+H)+; HRMS: calcd for C10H11Br2O3: 336.9075; found:
336.9084.
2-Iodo-1-(2,4-dimethoxyphenyl)ethanone (15). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NIS,
r.t. = 10 min, 55 °C, preparative chromatography SiO2, CH2Cl2, brown solid (34%), mp: 64.5–67.0 °C

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(lit [48] 55–57.5 °C); 1H-NMR (CDCl3): δ 7.91 (d, J = 8.8 Hz, 1H), 6.56 (dd, J = 8.8 Hz, J = 2.3 Hz,
1H), 6.47 (d, J = 2.3 Hz, 1H), 4.46 (s, 2H), 3.94 (s, 3H), 3.87 (s, 3H); IR (KBr): 3009, 2940, 2838,
1657, 1595, 1499, 1454, 1414, 1333, 1267, 1211, 1161, 1109, 1023, 984, 826, 610 cm−1; MS m/z (CI):
307.0 (M+H)+.
1-Acetyl-5-iodo-2,4-dimethoxybenzene (16). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NIS, r.t.
= 10 min, 55 °C, preparative chromatography SiO2, CH2Cl2, grey solid (3%), mp: 130.3–134.0 °C (lit
1
[48] 142–145 °C); H-NMR (CDCl3): δ 8.23 (s, 1H), 6.39 (s, 1H), 3.94 (s, 3H), 3.94 (s, 3H), 2.56 (s,
3H); IR (KBr): 1647, 1591, 1464, 1391, 1357, 1321, 1271, 1231, 1022, 830 cm−1; MS (ESI): 307.0
(M+H)+, HRMS: calcd for C10H12IO3: 306.9831; found: 306.9821.
2-Iodo-1-(5-iodo-2,4-dimethoxyphenyl)ethanone (17). One mmol of substrate, 3 mmol IL-A, 1.1 mmol
NIS, r.t. = 10 min, 55 °C; preparative chromatography SiO2, CH2Cl2); yellow solid (8%); mp:
145.8–148.6 °C; 1H-NMR (CDCl3): δ 8.32 (s, 1H), 6.41 (s, 1H), 4.42 (s, 2H), 4.00 (s, 3H), 3.97 (s, 3H);
13C-NMR (CD3COCD3): δ 192.0, 165.2, 163.6, 143.4, 120.4, 98.1, 76.4, 58.4, 57.8, 10.7; IR (KBr):
1635, 1585, 1464, 1403, 1389, 1329, 1262, 1213, 1017, 919, 818 cm−1; MS (ESI): 432.9 (M + H)+;
HRMS: calcd for C10H11I2O3: 432.8798; found: 432.8788.
2-Iodo-1-(2,6-dimethoxyphenyl)ethanone (19). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NIS,
r.t. = 10 min, 55 °C, preparative chromatography SiO2, CH2Cl2, yellow solid (47%), mp: 51.7–54.6 °C
1
(lit [48] 58–60.5 °C); H-NMR (CDCl3): δ 7.31 (t, J = 8.4 Hz, 1H), 6.57 (d, J = 8.4 Hz, 2H), 4.30
(s, 2H), 3.83 (s, 6H); IR (KBr): 2937, 2837, 1713, 1593, 1474, 1429, 1378, 1307, 1284, 1250, 1161,
1121, 1091, 980, 773, 722 cm−1; MS (ESI): 307.0 (M+H)+.
2-Iodo-1-(3-iodo-2,6-dimethoxyphenyl)ethanone (20). One mmol of substrate, 3 mmol IL-A, 1.1 mmol
NIS, r.t. = 10 min, 55 °C; preparative chromatography SiO2, CH2Cl2; yellow oil (10%);
1H-NMR (CDCl3): δ 7.75 (d, J = 8.8 Hz, 1H), 6.55 (d, J = 8.8 Hz, 1H), 4.31 (s, 2H), 3.84 (s, 3H), 3.82
(s, 3H); 13C-NMR (CD3COCD3): δ 195.4, 159.9, 159.0, 143.0, 125.0, 111.8, 82.0, 64.5, 57.9, 11.1; IR
(NaCl): 2967, 2938, 2838, 1694, 1574, 1462, 1433, 1395, 1282, 1244, 1165, 1084, 1003, 913, 805
cm−1; MS (ESI): 432.9 (M + H)+: HRMS: calcd for C10H11I2O3: 432.8798; found: 432.8788.
2,2-Dichloro-1-(3,5-dichloro-2,6-dimethoxyphenyl)ethanone (21). One mmol of substrate, 3 mmol IL-A,
4.4 mmol NCS, r.t. = 1080 min, 85 °C; preparative chromatography SiO2, hexane/CH2Cl2 = 1/1; white
1
solid (65%); mp: 53.4–54.4 °C; H-NMR (CD3COCD3): δ 7.77 (s, 1H), 6.92 (s, 1H), 3.92 (s, 6H);
13C-NMR (CD3COCD3): δ 189.0, 154.8, 135.5, 129.7, 125.4, 72.5, 64.3; IR (KBr): 3016, 2946, 1738,
1568, 1462, 1414, 1214, 1070, 984, 926, 872, 818, 773, 714, 641 cm−1; Anal. Calcd for C10H8Cl4O3: C,
37.77; H, 2.54. Found: C, 37.89; H, 2.36.
1-Acetyl-3-bromo-2,6-dimethoxybenzene (22). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NBS,
1
r.t. = 10 min, 55 °C, preparative chromatography SiO2, CH2Cl2, yellow oil [64] (63%); H-NMR
(CDCl3): δ 7.48 (d, J = 8.9 Hz, 1H), 6.61 (d, J = 8.9 Hz, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 2.49 (s, 3H);
IR(NaCl): 3004, 2940, 2873, 2839, 1707, 1580, 1464, 1401, 1351, 1285, 1240, 1219, 1183, 1092,
1007, 971, 910, 801, 689, 652 cm−1; MS (ESI): 259.0 (M+H)+, 261.0 (M+2+H)+.

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2-Bromo-1-(3-bromo-2,6-dimethoxyphenyl)ethanone (23). One mmol of substrate, 3 mmol IL-A,
1.1 mmol NBS, r.t. = 10 min, 55 °C; preparative chromatography SiO2, CH2Cl2; yellow oil (8%);
1H-NMR (CDCl3): δ 7.54 (d, J = 8.9 Hz, 1H), 6.64 (d, J = 8.9 Hz, 1H), 4.36 (s, 2H), 3.85 (s, 3H), 3.83
(s, 3H); 13C-NMR (CD3COCD3): δ 194.5, 158.9, 156.4, 137.1, 125.7, 111.1, 109.4, 64.1, 57.9, 38.6; IR
(NaCl): 2941, 1707, 1580, 1464, 1403, 1285, 1227, 1180, 1132, 1088, 1005, 916, 803 cm−1; MS (ESI):
336.9 (M+H)+, 338.9 (M+2+H)+, 340.9 (M+4+H)+; HRMS: calcd for C10H11Br2O3: 336.9075; found:
336.9082.
2,2-Dibromo-1-(3,5-dibromo-2,6-dimethoxyphenyl)ethanone (24). One mmol of substrate, 3 mmol IL-A,
4.4 mmol NBS, r.t. = 360 min, 85 °C; preparative chromatography SiO2, hexane/CH2Cl2 = 1/1); white
1
solid (72%); mp: 54.9–57.6 °C; H-NMR (CD3COCD3): δ 8.05 (s, 1H), 6.88 (s, 1H), 3.90 (s, 6H);
13C-NMR (CD3COCD3): δ 188.5, 156.6, 140.9, 129.5, 114.4, 64.5, 45.2; IR (KBr): 3017, 2939, 1723,
1559, 1456, 1406, 1275, 1220, 1165, 1066, 982, 916, 799 615 cm−1; MS (ESI): 494.7 (M+2+H)+,
496.7 (M+4+H)+, 498.7 (M+6+H)+; HRMS: calcd for C10H9Br4O3: 492.7285; found: 492.7296; Anal.
Calcd for C10H8Br4O3: C, 24.23; H, 1.63. Found: C, 24.37; H, 1.61.
2-Iodo-1-(2,3,4-trimethoxyphenyl)ethanone (26). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NIS,
1
r.t. = 60 min, 55 °C, preparative chromatography SiO2, CH2Cl2, yellow oil [63] (68%); H-NMR
(CDCl3): δ 7.59 (d, J = 8.9 Hz, 1H), 6.73 (d, J = 8.9 Hz, 1H), 4.49 (s, 2H), 4.07 (s, 3H), 3.92 (s, 3H),
3.87 (s, 3H); IR (NaCl): 2941, 2840, 1661, 1587, 1493, 1464, 1410, 1287, 1212, 1096, 1005, 924, 881,
808, 697 cm−1; MS (ESI): 337.0 (M+H)+.
2-Bromo-1-(2,3,4-trimethoxyphenyl)ethanone (27). One mmol of substrate, 3 mmol IL-A, 1.1 mmol
NBS, r.t. = 30 min, 55 °C, preparative chromatography SiO2, CH2Cl2, white solid [65] (44%), mp:
1
39.8–42.0 °C; H-NMR (CDCl3): δ 7.61 (d, J = 8.9 Hz, 1H), 6.74 (d, J = 8.9 Hz, 1H), 4.57 (s, 2H),
4.05 (s, 3H), 3.93 (s, 3H), 3.87 (s, 3H); IR (NaCl): 2941, 2843, 1680, 1589, 1493, 1464, 1410, 1294,
1213, 1099, 999, 809, 668 cm−1; MS (ESI): 289.0 (M+H)+, 291.0 (M+2+H)+.
2,2-Dibromo-1-(2,3,4-trimethoxyphenyl)ethanone (28). One mmol of substrate, 3 mmol IL-A, 1.1 mmol
NBS, r.t. = 30 min, 55 °C; preparative chromatography SiO2, CH2Cl2; white solid (14%); mp:
42.9–44.6 °C; 1H-NMR (CDCl3): δ 7.64 (d, J = 9.0 Hz, 1H), 7.09 (s, 1H), 6.76 (d, J = 9.0 Hz, 1H), 4.08
(s, 3H), 3.94 (s, 3H), 3.87 (s, 3H); 13C-NMR (CD3COCD3): δ 188.2, 161.0, 155.5, 143.7, 128.8, 121.3,
109.9, 63.6, 62.0, 57.7, 46.5; IR (KBr): 3020, 2942, 1682, 1588, 1495, 1462, 1410, 1293, 1217, 1097,
989, 814, 687 cm−1; MS (ESI): 366.9 (M+H)+, 368.9 (M+2+H)+, 370.9 (M+4+H)+; HRMS: calcd for
C11H13Br2O4: 366.9181; found: 366.9175; Anal. Calcd for C11H12Br2O4: C, 35.90; H, 3.29. Found: C,
36.29; H, 3.29.
2-Bromo-1-(5-bromo-2,3,4-trimethoxyphenyl)ethanone (29). One mmol of substrate, 3 mmol IL-A,
2.2 mmol NBS, r.t. = 120 min, 70 °C; preparative chromatography SiO2, CH2Cl2; colorless oil (37%);
1H-NMR (CDCl3): δ 7.75 (s, 1H), 4.52 (s, 2H), 4.05 (s, 3H), 3.99 (s, 3H), 3.90 (s, 3H); 13C-NMR
(CD3COCD3): δ 191.6, 157.3, 155.8, 149.2, 129.8, 128.0, 113.0, 63.2, 62.5, 62.5, 38.6; IR(NaCl):
3073, 2942, 1692, 1574, 1462, 1403, 1304, 1260, 1223, 1092, 1051, 995, 932, 889, 872, 791, 674

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cm−1; MS (ESI): 366.9 (M+H)+, 368.9 (M+2+H)+, 370.9 (M+4+H)+; HRMS: calcd for C11H13Br2O4:
366.9181; found: 366.9186; Anal. Calcd for C11H12Br2O4: C, 35.90; H, 3.29. Found: C, 35.91; H, 3.15.
2,2-Dibromo-1-(5-bromo-2,3,4-trimethoxyphenyl)ethanone (30). One mmol of substrate, 3 mmol IL-A,
3.3 mmol NBS, r.t. = 120 min, 70 °C; preparative chromatography SiO2, hexane/CH2Cl2 = 1/9); yellow
oil (88%); 1H-NMR (CD3COCD3): δ 7.70 (s, 1H), 7.22 (s, 1H), 4.11 (s, 3H), 4.00 (s, 3H), 3.94 (s, 3H);
13C-NMR (CD3COCD3): δ 187.6, 157.8, 155.5, 149.0, 130.4, 125.3, 113.2, 63.7, 62.6, 62.6, 45.9; IR
(NaCl): 2943, 1690, 1574, 1463, 1403, 1304, 1258, 1216, 1090, 1047, 993, 797, 669 cm−1; MS (ESI):
444.8 (M+H)+, 446.8 (M+2+H)+, 448.8 (M+4+H)+, 450.8 (M+6+H)+; HRMS: calcd for C11H12Br3O4:
444.8286; found: 444.8291; Anal. Calcd for C11H11Br3O4: C, 29.56; H, 2.48. Found: C, 29.44; H, 2.27.
p-Iodoanisole (32a). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NIS, r.t. = 20 min, 55 °C,
preparative chromatography SiO2, hexane/CH2Cl2 = 7.5/2.5, white solid (84%), mp: 42.1–44.4 °C
1
(lit [48] 47–49.5 °C); H-NMR (CDCl3): δ 7.55 (d, J = 9.0 Hz, 2H), 6.68 (d, J = 9.0 Hz, 2H), 3.78
(s, 3H); IR (KBr): 2965, 2936, 2835, 1584, 1481, 1450, 1285, 1244, 1173, 1026, 993, 807 cm−1.
p-Bromoanisole (32b). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NBS, r.t. = 20 min, 55 °C, CC
(SiO2, hexane, colorless oil [9] (81%); 1H-NMR (CDCl3): δ 7.37 (d, J = 9.0 Hz, 2H), 6.78 (d, J = 9.0 Hz,
2H), 3.78 (s, 3H); IR (NaCl): 3004, 2957, 2937, 2903, 2835, 1579, 1487, 1460, 1290, 1249, 1171,
1072, 1032, 1003, 822 cm−1.
p-Chloroanisole (32c). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NCS, r.t. = 30 min, 55 °C,
1
preparative chromatography SiO2, hexane/CH2Cl2 = 7.5/2.5, colorless oil [66] (78%); H-NMR
(CDCl3): δ 7.24 (d, J = 9.0 Hz, 2H), 6.83 (d, J = 9.0 Hz, 1H), 3.79 (s, 3H); IR (NaCl): 3006, 2959,
2940, 2906, 2837, 1593, 1492, 1460, 1290, 1245, 1181, 1169, 1092, 1063, 1032, 824, 750, 686, 639,
626 cm−1.
2,4-Diiodoanisole (33a). One mmol of substrate, 3 mmol IL-A, 2.2 mmol NIS, r.t. = 30 min, 70 °C,
CC (SiO2, CH2Cl2, white solid (92%), mp: 65.8–67.0 °C (lit [67] 67.5–68.5 °C); 1H-NMR (CDCl3): δ
8.04 (d, J = 2.1 Hz, 1H), 7.58 (dd, J = 8.6 Hz, J = 2.1 Hz, 1H), 6.58 (d, J = 8.6 Hz, 1H), 3.86 (s, 3H);
IR (KBr): 1582, 1469, 1429, 1275, 1246, 1182, 1142, 1034, 866, 797, 656 cm−1.
2,4-Dibromoanisole (33b). One mmol of substrate, 3 mmol IL-A, 2.2 mmol NBS, r.t. = 180 min,
85 °C, CC SiO2, hexane/CH2Cl2 = 7.5/2.5, white solid (90%), mp: 53.5–56.0 °C (lit [67] 61–62 °C);
1H-NMR (CDCl3): δ 7.67 (d, J = 2.3 Hz, 1H), 7.38 (dd, J = 8.8 Hz, J = 2.3 Hz, 1H), 6.77 (d, J = 8.8 Hz,
1H), 3.88 (s, 3H); IR (NaCl): 3080, 2973, 2936, 2835, 1574, 1476, 1456, 1379, 1289, 1250, 1052,
1020, 876, 804, 679, 619 cm−1.
2,4-Dichloroanisole (33c). One mmol of substrate, 3 mmol IL-A, 2.2 mmol NCS, r.t. = 30 min, 70 °C,
CC SiO2, hexane/CH2Cl2 = 7.5/2.5, colorless oil [66] (89%); 1H-NMR (CDCl3): δ 7.37 (d, J = 2.5 Hz,
1H), 7.19 (dd, J = 8.8 Hz, J = 2.5 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 3.89 (s, 3H); IR (NaCl): 3075,
3011, 2965, 2940, 2901, 2841, 1580, 1484, 1439, 1389, 1292, 1263, 1184, 1106, 1065, 1025, 870, 835,
805, 716, 642 cm−1.

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1,5-Diiodo-2,4-dimethoxybenzene (35a). One mmol of substrate, 3 mmol IL-A, 2.2 mmol NIS,
r.t. = 20 min, 70 °C, column chromatography (SiO2, CH2Cl2, white solid (89%), mp: 193.6–196.5 °C
1
(lit [68] 201–202 °C); H-NMR (CDCl3): δ 8.04 (s, 1H), 6.37 (s, 1H), 3.89 (s, 6H); IR (neat): 1568,
1556, 1458, 1452, 1428, 1357, 1275, 1207, 1177, 1034, 1014, 886, 813, 652 cm−1; MS (ESI): 389.9 (M)+.
1,5-Dibromo-2,4-dimethoxybenzene (35b). One mmol of substrate, 3 mmol IL-A, 2.2 mmol NBS, r.t. =
30 min, 70 °C, preparative chromatography SiO2, hexane/CH2Cl2 = 2.5/7.5, white solid (70%), mp:
135.5–138.4 °C (lit [69] 138–139 °C); 1H-NMR (CDCl3): δ 7.66 (s, 1H), 6.50 (s, 1H), 3.91 (s, 6H); IR
(neat): 1579, 1570, 1487, 1463, 1432, 1367, 1287, 1208, 1175, 1061, 1052, 1019, 877, 864, 813, 805,
687, 680 cm−1.
1,5-Dichloro-2,4-dimethoxybenzene (35c). One mmol of substrate, 3 mmol IL-A, 2.2 mmol NCS,
r.t. = 120 min, 70 °C, preparative chromatography SiO2, hexane/CH2Cl2 = 2.5/7.5, white solid (82%),
1
mp: 111.6–114.2 °C (lit [70] 118–119 °C); H-NMR (CDCl3): δ 7.36 (s, 1H), 6.54 (s, 1H), 3.91 (s,
6H); IR (neat): 1738, 1578, 1492, 1466, 1454, 1428, 1374, 1295, 1229, 1206, 1171, 1085, 1021, 861, 804,
740 cm−1.
2,4,4-Trichloro-5-methoxycyclohexa-2,5-dienone (36). One mmol of substrate, 3 mmol IL-A, 3.3 mmol
NCS, r.t. = 45 min, 70 °C; preparative chromatography SiO2, hexane/CH2Cl2 = 2.5/7.5; yellow solid
1
13
(84%); mp: 114.6–116.2 °C; H-NMR (CDCl3): δ 7.13 (s, 1H), 5.65 (s, 1H), 3.94 (s, 3H); C-NMR
(CD3COCD3): δ 178.3, 169.5, 139.7, 132.4, 101.2, 76.3, 59.3; IR (neat): 1738, 1657, 1595, 1459,
1347, 1269, 1217, 1156, 1034, 974, 934, 898, 838, 783, 698, 686, 608 cm−1; MS (ESI): 226.9 (M+H)+,
228.9 (M+2+H)+, 230.9 (M+4+H)+; HRMS: calcd for C7H6Cl3O2: 226.9433; found: 226.9431; Anal.
Calcd for C7H5Cl3O2: C, 36.96; H, 2.22. Found: C, 37.13; H, 2.23.
p-Iodotoluene+o-Iodotoluene (38a, 39a). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NIS, r.t. =
20 min, 55 °C, preparative chromatography SiO2, hexane/CH2Cl2 = 99.7/0.3, yellow oil [71] (49%);
1H-NMR (CDCl3): δ 7.80 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.23 (d, J = 4.1 Hz, 2H), 6.92
(d, J = 8.1 Hz, 2H), 6.90-6.82 (m, 1H), 2.43 (s, 3H), 2.29 (s, 3H).
p-Bromotoluene+o-Bromotoluene (38b, 39b). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NBS,
1
r.t. = 20 min, 55 °C; H-NMR (CDCl3): δ 7.55–7.49 (m, 1H), 7.36 (d, J = 8.3 Hz, 2H), 7.29–7.14
(m, 2H), 7.08–6.99 (m, 3H), 2.40 (s, 3H), 2.30 (s, 3H) [72].
p-Chlorotoluene+o-Chlorotoluene (38c, 39c). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NCS,
1
r.t. = 180 min, 70 °C; H-NMR (CDCl3): δ 7.37–7.31 (m, 1H), 7.25–7.07 (m, 7H), 2.39 (s, 3H), 2.32
(s, 3H) [73].
5-Iodo-2-methylthiophene (41). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NIS, r.t. = 10 min,
1
55 °C, CC SiO2, hexane/CH2Cl2 = 7.5/2.5), yellow oil [74] (81%); H-NMR (CDCl3): δ 7.00
(d, J = 3.5 Hz, 1H), 6.44 (dq, J = 3.5 Hz, J = 0.9 Hz, 1H), 2.49 (d, J = 0.9 Hz, 3H).

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3.3. Scale up Experiment
To a stirred mixture of acetophenone (1, 9 mmol, 1.08 g) in IL-A (27 mmol, 9.95 g), N-bromo
succinimide (19.8 mmol, 3.52 g) was added. The reaction mixture was stirred at 70 °C for 40 min.
Then the mixture was cooled to room temperature and washed three times with dichloromethane. The
combined organic fractions were washed with aqueous Na2S2O3 and NaHCO3, dried over anhydrous
Na2SO4 and filtered. Solvent was removed under reduced pressure and the crude reaction mixture was
1
analyzed with H-NMR. Purification of crude reaction mixture by chromatography yielded 2.25 g
(90%) of 3b.
3.4. Recycling/Reuse of IL-A in Iodination of Acetophenone (1) with NIS
To a stirred mixture of acetophenone (1, 1 mmol, 120 mg) in IL-A (3 mmol, 368 mg), N-iodo
succinimide (1.1 mmol, 225 mg) was added. The reaction mixture was stirred at 55 °C for 10 minutes.
Then the mixture was cooled to room temperature and washed three times with dichloromethane. The
combined organic fractions were washed with aqueous Na2S2O3 and NaHCO3, dried over anhydrous
Na2SO4 and filtered. Solvent was removed under reduced pressure and the crude reaction mixture was
1
analyzed with H-NMR. Purification of crude reaction mixture with chromatography yielded 212 mg
(86%) of 2a. The IL-A from reaction was dried under reduced pressure and reused.
4. Conclusions
In summary, the Brønsted acidic ionic liquid 1-methyl-3-(4-sulfobutyl)imidazolium triflate
([BMIM(SO3H)][OTf]; IL-A) exhibited a notable catalytic effect in the halofunctionalization of
aromatics with NXS and transformations were significantly faster as compared to IL-B. Aryl methyl
ketones were α- and α,α-dihalogenated with high selectivity and in respectable yields. In the case of
methoxy-substituted acetophenones, competing ring halogenation occurred. Activated arenes were
selectively mono- and dihalogenated. A noteworthy feature is exclusive para-halogenation of anisole
with NXS/IL-A. Recycling and reuse of [BMIM(SO3H)][OTf] was demonstrated in a prototype
iodination reaction in eight cycles with no decrease in the conversion. The catalytic role of IL-A in
dibromination with NBS is manifested in higher mono- to dihalogenation ratios when the reaction is
repeated in the used IL. The feasibility for scale-up was also demonstrated in a representative case.
Acknowledgments
The authors are grateful to the staff of the Mass Spectroscopy Centre at Jožef Stefan Institute for
mass spectrometric measuraments and prof. B. Stanovnik for elemental analysis. The Slovenian
Research Agency (contracts: Programme ARRS P1-0134, Young Researchers Fellowship ARRS
1000-08-310039, and USA/Si bilateral project BI-US/12-13-004) and European Regional
Development Found (OP 13.1.1.2.02.0005) are acknowledged for financial support.

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Sample Availability: Samples of all the compounds except 16, 17, 20, 23, 28, 38a–c, 39a–c and 41 are
available from the authors.
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