Reactivity of substrates with multiple competitive reactive sites toward NBS under neat reaction conditions promoted by visible light

Article abstract of DOI:10.1007/s11696-021-01711-x

Regioselectivity of visible-light-induced transformations of a range of (hetero)aryl alkyl-substituted ketones bearing several competitive reactive sites (α-carbonyl, benzyl and aromatic ring) with N-bromosuccinimide (NBS) was studied under solvent-free reaction conditions (SFRC) and in the absence of inert-gas atmosphere, radical initiators and catalysts. An 8-W energy-saving household lamp was used for irradiation. Heterogeneous reaction conditions were dealt with throughout the study. All substrates were mono- or dibrominated at the α-carbonyl position, and additionally, some benzylic or aromatic bromination was observed in substrates with benzylic carbon atoms or electron-donating methoxy groups, respectively. Surprisingly, ipso-substitution of the acyl group with a bromine atom took place with (4-methoxynaphthyl) alkyl ketones. While the addition of the radical scavenger TEMPO (2,2,6,6-tetramethylpiperidin-1-yloxy) decreased the extent of α- and ring bromination, it completely suppressed the benzylic bromination and α,α-dibromination with NBS under SFRC.

Full text of DOI:10.1007/s11696-021-01711-x

Chemical Papers
https://doi.org/10.1007/s11696-021-01711-x
ORIGINAL PAPER
Reactivity of substrates with multiple competitive reactive sites
toward NBS under neat reaction conditions promoted by visible light
Blaž Grjol1 · Marjan Jereb2
Received: 23 December 2020 / Accepted: 21 May 2021
© The Author(s) 2021
Abstract
Regioselectivity of visible-light-induced transformations of a range of (hetero)aryl alkyl-substituted ketones bearing sev-
eral competitive reactive sites (α-carbonyl, benzyl and aromatic ring) with N-bromosuccinimide (NBS) was studied under
solvent-free reaction conditions (SFRC) and in the absence of inert-gas atmosphere, radical initiators and catalysts. An 8-W
energy-saving household lamp was used for irradiation. Heterogeneous reaction conditions were dealt with throughout the
study. All substrates were mono- or dibrominated at the α-carbonyl position, and additionally, some benzylic or aromatic
bromination was observed in substrates with benzylic carbon atoms or electron-donating methoxy groups, respectively.
Surprisingly, ipso-substitution of the acyl group with a bromine atom took place with (4-methoxynaphthyl) alkyl ketones.
While the addition of the radical scavenger TEMPO (2,2,6,6-tetramethylpiperidin-1-yloxy) decreased the extent of α- and
ring bromination, it completely suppressed the benzylic bromination and α,α-dibromination with NBS under SFRC.
Keywords Halogenation · Photochemistry · Solvent-free reaction conditions · NBS · Regioselectivity
Introduction
reactions under (SFRC) have been reviewed in both older
and more recent literature (Cave et al. 2001; Martins et al.
2009; Singh and Chowdhury 2012; Gawande et al. 2014;
Obst and König 2018; Zagande and Patil 2019).
Solvent-free reaction conditions (SFRC) (Tanaka and Toda
2000; Metzger 1998) are alternative reaction conditions
to the transformations in solution (Reichardt 2007) and
attracted considerable attention due to important advantages.
Shorter reaction times, lower consumption of organic sol-
vents, simple isolation/purifcation procedures and less reac-
tion waste are some of notable advantages. Nonconventional
reaction media, such as water, supercritical CO2 or ionic liq-
uids, are also a promising replacement for organic solvents
(Adams et al. 2004). Another alternative is to perform reac-
tions under highly concentrated reaction conditions (Walsh
et al. 2007) or in the presence of a small amount of solvent
vapor (Nakamatsu et al. 2005). A great number of diferent
N-bromosuccinimide (NBS) is one of the most com-
mon and versatile reagents in organic chemistry (Djerassi
1948; Paquette et al. 2009). It is easy to handle, inexpen-
sive, readily available, non-toxic, and usually more selective
than bromine. Traditional methods of bromination include
molecular bromine or bromides under harsh reaction condi-
tions, even though unconventional methods, for instance,
in water (Shaw et al. 1997; Tanaka et al. 1999) or under
SFRC (Toda and Schmeyers 2003; Pravst et al. 2009; Wang
and Gao 2012), have been developed. In a more alterna-
tive approach, transformations with NBS are performed
under microwave and ultrasound irradiation (Heropoulos
et al. 2007), on water (Podgoršek et al. 2006), in ionic liq-
uids (Togo and Hirai 2003; Ganguly et al. 2005), scCO2
(Tanko and Blackert 1994) and bio-waste extract (Appa et al.
2019). Under SFRC, aromatic (Prakash et al. 2004; Iman-
zadeh et al. 2006), Wohl–Ziegler (Winkler et al. 2014) and
α-bromination of carbonyl compounds (Kumar et al. 2012;
Pravst et al. 2008) have been reported, but these methods still
require the use of acid catalysts or radical initiators. While
more activated substrates react in the absence of catalysts
In memory of Dr. Miha Tišler (1926–2021), Professor Emeritus of
University of Ljubljana.
* Marjan Jereb
marjan.jereb@fkkt.uni-lj.si
1
Present Address: Kilobaser GmbH, Reininghausstrasse 13a,
8020 Graz, Austria
2
Faculty of Chemistry and Chemical Technology, University
of Ljubljana, Ljubljana, Večna pot 113, 1000, Slovenia
Vol.:(0123456789)
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Chemical Papers
or initiators (Rahman et al. 2005; Pravst et al. 2006a, b, 8;
Bose and Mal 2014), other methods make the use of alter-
native modes of activation, such as microwave irradiation
(Goswami et al. 2004) or concentrated solar radiation (Dinda
et al. 2013; Deshpande et al. 2015). Photo-induced transfor-
mations with NBS have been extensively studied in solvents
(Arbuj et al. 2007; Šterk et al. 2013; Cantillo et al. 2014);
however, to the best of our knowledge there are rare reports
on these reactions under SFRC (Jereb et al. 2009).
Reactions were performed in closed fasks without inert
atmosphere. The experimental procedure was the same for
liquid and solid ketones: NBS was added to the substrate
and the reaction mixture was stirred with a small stirring
bar under solvent-free reaction conditions (SFRC). Reac-
tion mixtures with solid ketones turned into a molten state
and the reaction proceeded as efciently as the reactions
with liquid substrates. An 8-W energy-saving lamp was
used throughout all the experiments, and the average reac-
tion temperature was 27 °C. The experiments in the dark
were carried out at 27 °C. The progress of the reactions
was monitored by thin-layer chromatography (TLC). Light
source: Philips Genie 8 W energy-saving light bulb. Column
chromatography (CC): silica gel 60 (63–200 mm, 70–230
mesh ASTM; Fluka); CH2Cl2/petroleum ether (1:3). Pre-
parative thin-layer chromatography (TLC): Merck-60-F254
plates; mixtures of light petroleum ether (b.p. 40–60 °C) and
CH2Cl2. NMR spectra: Bruker DPX 300 (300 MHz) and
Bruker AVANCE III (500 MHz) instruments; in CDCl3; δ in
ppm relative to TMS as internal standard for 1H NMR and to
the central line of CDCl3 (δ=77.00 ppm) for 13C NMR, J in
Hz. IR spectra: Bruker Alpha FT-IR spectrometer; in cm−1.
HRMS: Agilent 6224 Accurate Mass TOF LC/MS system
spectrometer; electrospray ionization; in m/z. Elemental
analysis: Perkin Elmer CHNS/O Analyzer 2400 Series II
elemental analyzer. Melting points: Büchi 535 melting point
apparatus; uncorrected.
Molecular motion in solvent-free reactions is restricted,
and the aggregate state of the reaction mixture plays an
important role in SFRC transformations. Whereas mole-
cules are more mobile in liquid/solid systems, between two
solid reagents, the formation of a melt phase is crucial for
increased molecular mobility (Rothenberg et al. 2001). More
so than the aggregate state, the structure of the substrates
largely afects the reactivity and selectivity of transforma-
tions. We have previously shown that a 40-W tungsten lamp
promotes benzylic-, ring- or α-carbonyl bromination by NBS
under SFRC (Jereb et al. 2009). One might wonder how
selective bromination under visible-light conditions would
be when a competitive aromatic-, radical- and α-carbonyl
substitution was possible in a single substrate. Studies
addressing this issue have been reported (Pravst et al. 2006a,
b, 47; Podgoršek et al. 2009; Vražič et al. 2013), but in those
cases regioselectivity of functionalization was modulated
through careful tuning of the reaction conditions. To our
knowledge, regioselectivity of visible-light-induced transfor-
mations of substrates containing several competitive reactive
sites with NBS under SFRC remains unexplored.
General procedure for photo‑induced reactions
with NBS under SFRC
In the present study, we investigated photochemical
transformations of diverse aryl-substituted ketones with
NBS under solvent-free reaction conditions: with an 8-W
energy-saving lamp as an activation source, in the absence
of any solvents, radical initiators and catalysts and in the
presence of air. For testing the substrate scope, we selected
a broad range of liquid and solid ketones that contained dif-
ferent functional groups, which could have an infuence on
the type of transformation.
To a ketone (0.3 mmol), NBS (0.33 or 0.66 mmol, 20 or
39 mg) was added and the resulted reaction mixture was
stirred under illumination with an 8-W energy-saving light
bulb for 19–29 h. At the end of the reaction, conversions and
the product distribution were determined by 1H NMR spec-
troscopy of the crude reaction mixture. Pure products were
obtained after separation by either CC or preparative TLC
and were analyzed by 1H NMR, 13C NMR, IR, HRMS and
melting point when solid. Spectroscopic data of the known
compounds are available in Supporting Information and are
in accordance with the literature data.
Experimental
General information
Characterization of the new products
Reagents and solvents were obtained from commercial
sources. NBS was recrystallized from a mixture of CH2Cl2/
petroleum ether, and solvents were used as received. All
ketones were prepared by the method of the classical Frie-
del–Crafts acylation (Vogel et al. 1989). 14 was prepared
according to the published procedure (Coan and Becker
1955).
2‑Bromo‑1‑(4‑(isopropyl)phenyl)ethanone 2c.
1c (0.049 g, 0.3 mmol), NBS (0.059 g, 0.33 mmol). Column
chromatography on silica gel (Rf =0.55, CH2Cl2/petroleum
ether 1:3 → 2:1). Colorless oil (0.028 g, 39%). IR (neat):
ν 2961, 1676, 1604, 1569, 1461, 1416, 1310, 1278, 1198,
1
−1
1186, 1056, 1009, 990, 846, 822, 677, 661 cm . H NMR
(500 MHz, CDCl3): δ 1.28 (d, J=6.9 Hz, 6H), 2.98 (sept,
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Chemical Papers
1
−1
J=6.9 Hz, 1H), 4.44 (s, 2H), 7.35 (d, J=8.3 Hz, 2H), 7.93
(d, J=8.3 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ 23.6,
30.9, 34.3, 127.0, 129.2, 131.8, 155.7, 190.9. HRMS (ESI-
TOF, m/z): found 241.0223 ([M+ H]+, C11H14BrO+; calc.
241.0223).
770, 742, 709, 682 cm . H NMR (300 MHz, CDCl3): δ
1.29 (d, J = 6.9 Hz, 6H), 2.99 (sept, J = 6.9 Hz, 1H), 6.69
(s, 1H), 7.36 (d, J = 8.4 Hz, 2H), 8.02 (d, J = 8.4 Hz, 2H).
13C NMR (75 MHz, CDCl3): δ 23.5, 34.4, 39.8, 127.1,
128.5, 130.0, 156.3, 185.6. HRMS (ESI-TOF, m/z): found
318.9330 ([M + H]+, C11H14Br2O+; calc. 318.9328).
2‑Bromo‑1‑(3‑methyl‑4‑methoxyphenyl)ethanone 2e.
1e (0.049 g, 0.3 mmol), NBS (0.059 g, 0.33 mmol). Col-
umn chromatography on silica gel (Rf =0.47, CH2Cl2/petro-
leum ether 1:3→2:1). Colorless solid (0.013 g, 18%). M.p.
45–48 °C. IR (neat): ν 2941, 1683, 1596, 1497, 1438, 1410,
2,2‑Dibromo‑1‑(4‑(cyclohexyl)phenyl)ethanone 4d.
1d (0.061 g, 0.3 mmol), NBS (0.059 g, 0.33 mmol). Col-
umn chromatography on silica gel (Rf = 0.75, CH2Cl2/
petroleum ether 1:3 → 2:1). Colorless solid (0.003 g,
5%). M.p. 100–104 °C. IR (neat): ν 3027, 2920, 2848,
1683, 1600, 1566, 1445, 1416, 1315, 1273, 1212, 1191,
1
−1
1250, 1212, 1126, 1020, 878, 818, 752, 682, 611 cm . H
NMR (500 MHz, CDCl3): δ 2.26 (s, 3H), 3.91 (s, 3H), 4.40
(s, 2H), 6.87 (d, J=8.6 Hz, 1H), 7.80 (d, J=1.7 Hz, 1H),
7.86 (dd, J=1.7, 8.6 Hz, 1H). 13C NMR (125 MHz, CDCl3):
δ 16.3, 30.8, 55.6, 109.4, 126.4, 127.3, 129.3, 131.5, 162.4,
190.2. HRMS (ESI-TOF, m/z): found 243.0013 ([M+H]+,
1
−1
1145, 988, 841, 774, 707, 630 cm . H NMR (500 MHz,
CDCl3): δ 1.21–1.32 (m, 1H), 1.35–1.49 (m, 4H),
1.74–1.81 (m, 1H), 1.82–1.93 (m, 4H), 2.54–2.63 (m, 1H),
6.70 (s, 1H), 7.34 (d, J = 8.3 Hz, 2H), 8.01 (d, J = 8.3 Hz,
2H). 13C NMR (125 MHz, CDCl3): δ 25.9, 26.6, 33.9,
39.9, 44.8, 127.5, 128.4, 129.9, 155.5, 185.6. HRMS (ESI-
TOF, m/z): found 358.9634 ([M+H]+, C14H17Br2O+; calc.
358.9641).
+
C10H12BrO2 ; calc. 243.0015).
2‑Bromo‑1‑(3,5‑dimethyl‑4‑methoxyphenyl)ethanone 2f.
1f (0.053 g, 0.3 mmol), NBS (0.059 g, 0.33 mmol). Column
chromatography on silica gel (Rf =0.38, CH2Cl2/petroleum
ether 1:3→2:1). Pale yellowish solid (0.015 g, 19%). M.p.
43–45 °C. IR (neat): ν 2948, 1682, 1595, 1483, 1387, 1313,
2,2‑Dibromo‑1‑(3‑methyl‑4‑methoxyphenyl)ethanone 4e.
−1
1256, 1229, 1140, 1055, 1007, 887, 856, 769, 708, 641 cm .
1H NMR (500 MHz, CDCl3): δ 2.34 (s, 6H), 3.77 (s, 3H),
4.41 (s, 2H), 7.67 (s, 2H). 13C NMR (125 MHz, CDCl3): δ
16.3, 30.9, 59.7, 129.5, 130.0, 131.6, 162.0, 190.7. HRMS
1e (0.049 g, 0.3 mmol), NBS (0.059 g, 0.33 mmol). Col-
umn chromatography on silica gel (Rf =0.68, CH2Cl2/petro-
leum ether 1:3→2:1). Colorless solid (0.015 g, 29%). M.p.
113–115 °C. IR (neat): ν 3033, 2923, 1665, 1591, 1503,
1455, 1438, 1416, 1259, 1217, 1127, 1022, 987, 908, 814,
+
(ESI-TOF, m/z): found 257.0172 ([M+H]+, C11H14BrO2 ;
calc. 257.0172).
1
−1
761, 717, 680, 615 cm . H NMR (500 MHz, CDCl3): δ
2.26 (s, 3H), 3.92 (s, 3H), 6.70 (s, 1H), 6.88 (d, J=8.7 Hz,
1H), 7.88 (d, J=2.1 Hz, 1H), 7.97 (dd, J=2.1, 8.7 Hz, 1H).
13C NMR (125 MHz, CDCl3): δ 16.3, 40.0, 55.7, 109.5,
122.8, 127.6, 130.1, 132.2, 162.9, 184.9. HRMS (ESI-
2‑Bromo‑1‑(4‑(1‑bromoethyl)phenyl)ethanone 3b.
1b (0.044 g, 0.3 mmol), NBS (0.059 g, 0.33 mmol). Prepara-
tive TLC (Rf =0.45, CH2Cl2/petroleum ether 1:3). Brownish
solid (0.002 g, 4%). M.p. 48–53 °C. IR (neat): ν 2948, 1694,
1603, 1571, 1412, 1388, 1280, 1197, 1162, 1069, 1042,
+
TOF, m/z): found 320.9117 ([M+H]+, C10H11Br2O2 ; calc.
320.9120).
1
−1
989, 822, 681 cm . H NMR (300 MHz, CDCl3): δ 2.05
(d, J=6.9 Hz, 3H), 4.42 (s, 2H), 5.20 (q, J=6.9 Hz, 1H),
7.52–7.59 (m, 2H), 7.94–8.00 (m, 2H). 13C NMR (75 MHz,
CDCl3): δ 26.4, 30.6, 47.5, 127.4, 129.4, 133.7, 149.1,
190.6. HRMS (ESI-TOF, m/z): found 304.9168 ([M+H]+,
C10H11Br2O+; calc. 304.9171).
2,2‑Dibromo‑1‑(3,5‑dimethyl‑4‑methoxyphenyl)ethanone
4f.
1f (0.053 g, 0.3 mmol), NBS (0.059 g, 0.33 mmol). Col-
umn chromatography on silica gel (Rf = 0.48, CH2Cl2/
petroleum ether 1:3→2:1). Colorless solid (0.014 g, 25%).
M.p. 85–87 °C. IR (neat): ν 2940, 1688, 1593, 1479, 1310,
2,2‑Dibromo‑1‑(4‑(isopropyl)phenyl)ethanone 4c.
1
−1
1c (0.049 g, 0.3 mmol), NBS (0.059 g, 0.33 mmol). Col-
umn chromatography on silica gel (Rf = 0.68, CH2Cl2/
petroleum ether 1:3 → 2:1). Yellowish solid (0.011 g,
21%). M.p. 40–45 °C. IR (neat): ν 2961, 1684, 1599, 1567,
1460, 1414, 1311, 1270, 1223, 1198, 1055, 983, 850, 840,
1221, 1142, 994, 903, 776, 749, 715, 652 cm . H NMR
(500 MHz, CDCl3): δ 2.34 (s, 6H), 3.79 (s, 3H), 6.71 (s, 1H),
7.75 (s, 2H). 13C NMR (125 MHz, CDCl3): δ 16.3, 39.8,
59.8, 126.2, 130.7, 131.8, 162.5, 185.4. HRMS (ESI-TOF,
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Chemical Papers
m/z): found 334.9276 ([M + H]+, C11H13Br2O2+; calc.
CDCl3): δ 1.90 (d, J = 6.6 Hz, 3H), 4.50 (s, 2H), 5.26 (q,
J=6.6 Hz, 1H), 7.51 (d, J=8.2 Hz, 2H), 8.00 (d, J=8.2 Hz,
2H). 13C NMR (125 MHz, CDCl3): δ 20.0, 31.9, 41.4, 129.4,
129.4, 133.8, 143.4, 192.6. HRMS (ESI-TOF, m/z): found
304.9171 ([M+H]+, C10H11Br2O+; calc. 304.9171).
334.9277).
2‑Bromo‑1‑(4‑(methylthio)phenyl)propan‑1‑one 6c.
5c (0.054 g, 0.3 mmol), NBS (0.059 g, 0.33 mmol). Col-
umn chromatography on silica gel (Rf =0.60, CH2Cl2/hex-
ane 1:3 → 2:1). Pale brownish solid (0.053 g, 68%). M.p.
88–90 °C. IR (neat): ν 2988, 1666, 1583, 1405, 1346, 1247,
2‑Bromo‑2‑methyl‑1‑(4‑methylphenyl)propan‑1‑one 9a.
8a (0.049 g, 0.3 mmol), NBS (0.059 g, 0.33 mmol). Pre-
parative TLC (Rf =0.64, CH2Cl2/petroleum ether 1:3). Pale
yellowish oil (0.017 g, 23%). IR (neat): ν 2927, 1672, 1606,
−1
1192, 1164, 1093, 1058, 992, 944, 830, 768, 745, 689 cm .
1H NMR (500 MHz, CDCl3): δ 1.89 (d, J=6.6 Hz, 3H), 2.53
(s, 3H), 5.25 (q, J=6.6 Hz, 1H), 7.28 (d, J=8.5 Hz, 2H),
7.93 (d, J = 8.5 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ
14.7, 20.1, 41.4, 125.0, 129.3, 130.1, 146.9, 192.3. HRMS
(ESI-TOF, m/z): found 258.9785 ([M+H]+, C10H12BrOS+;
calc. 258.9787).
−1
1459, 1370, 1267, 1163, 1104, 978, 886, 827, 748, 677 cm .
1H NMR (500 MHz, CDCl3): δ 2.03 (s, 6H), 2.41 (s, 3H),
7.24 (d, J=8.2 Hz, 2H), 8.07 (d, J=8.2 Hz, 2H). 13C NMR
(125 MHz, CDCl3): δ 21.6, 31.7, 60.5, 128.8, 130.4, 131.9,
143.2, 196.3. HRMS (ESI-TOF, m/z): found 241.0221
([M+H]+, C11H14BrO+; calc. 241.0223).
2‑Bromo‑1‑(5‑methyl‑2‑methoxyphenyl)propan‑1‑one 6d.
2‑Bromo‑1‑(2,4‑dimethylphenyl)‑2‑methylpropan‑1‑one
5d (0.053 g, 0.3 mmol), NBS (0.059 g, 0.33 mmol). Col-
umn chromatography on silica gel (Rf =0.59, CH2Cl2/hexane
1:2→2:1). Yellowish oil (0.056 g, 73%). IR (neat): ν 2925,
1671, 1608, 1495, 1463, 1441, 1404, 1332, 1283, 1248,
9b.
8b (0.053 g, 0.3 mmol), NBS (0.059 g, 0.33 mmol). Col-
umn chromatography on silica gel (Rf =0.63, CH2Cl2/petro-
leum ether 1:3 → 2:1). Pale yellowish oil (0.041 g, 53%).
IR (neat): ν 2972, 2924, 1688, 1612, 1458, 1385, 1369,
1
−1
1178, 1160, 1136, 1020, 968, 809, 741, 607 cm . H NMR
(300 MHz, CDCl3): δ 1.85 (d, J=6.7 Hz, 3H), 2.31 (s, 3H),
3.89 (s, 3H), 5.53 (q, J=6.7 Hz, 1H), 6.86 (d, J=8.5 Hz,
1H), 7.23–7.31 (m, 1H), 7.49–7.54 (m, 1H). 13C NMR
(75 MHz, CDCl3): δ 20.2, 20.3, 48.0, 55.8, 111.5, 125.4,
130.4, 131.7, 134.5, 156.1, 196.6. HRMS (ESI-TOF, m/z):
1
−1
1257, 1126, 1102, 973, 875, 817 cm . H NMR (500 MHz,
CDCl3): δ 1.97 (s, 6H), 2.26 (s, 3H), 2.34 (s, 3H), 6.98–7.03
(m, 1H), 7.06 (s, 1H), 7.60 (d, J = 7.9 Hz, 1H). 13C NMR
(125 MHz, CDCl3): δ 20.1, 21.3, 30.7, 62.6, 125.5, 126.9,
131.8, 134.9, 135.9, 139.8, 202.2. HRMS (ESI-TOF, m/z):
found 255.0379 ([M+H]+, C12H16BrO+; calc. 255.0379).
+
found 257.0164 ([M+H]+, C11H14BrO2 ; calc. 257.0172).
2‑Bromo‑1‑(3‑bromo‑4,5‑dimethoxyphenyl)propan‑1‑one
6e.
2‑Bromo‑1‑(3‑methyl‑4‑methoxyphenyl)‑2‑methylpro‑
pan‑1‑one 9d.
5e (0.058 g, 0.3 mmol), NBS (0.059 g, 0.33 mmol). Column
chromatography on silica gel (Rf =0.42, CH2Cl2/petroleum
ether 1:3 → 2:1). Yellowish oil (0.024 g, 42%). IR (neat):
ν 2934, 1695, 1592, 1505, 1439, 1372, 1336, 1257, 1204,
8d (0.058 g, 0.3 mmol), NBS (0.059 g, 0.33 mmol). Prepara-
tive TLC (Rf =0.40, CH2Cl2/petroleum ether 1:5). Yellowish
oil (0.013 g, 16%). IR (neat): ν 2928, 1664, 1598, 1501,
1458, 1386, 1317, 1298, 1256, 1127, 1104, 1021, 986, 916,
1
−1
1158, 1045, 1024, 972, 897, 855, 790, 760, 630 cm . H
NMR (500 MHz, CDCl3): δ 1.91 (d, J=6.7 Hz, 3H), 3.90 (s,
3H), 3.92 (s, 3H), 5.40 (q, J=6.7 Hz, 1H), 7.03 (s, 1H), 7.06
(s, 1H). 13C NMR (125 MHz, CDCl3): δ 19.9, 45.6, 56.2,
56.3, 110.6, 113.2, 115.9, 130.8, 148.4, 151.7, 196.6. HRMS
1
−1
817, 760, 681, 617 cm . H NMR (500 MHz, CDCl3): δ
2.04 (s, 6H), 2.25 (s, 3H), 3.90 (s, 3H), 6.83 (d, J=8.7 Hz,
1H), 7.99 (d, J = 2.0 Hz, 1H), 8.15 (dd, J = 2.0, 8.7 Hz,
1H). 13C NMR (125 MHz, CDCl3): δ 16.3, 32.0, 55.5, 60.6,
108.7, 126.4, 126.4, 130.6, 133.1, 161.3, 195.2. HRMS (ESI-
+
(ESI-TOF, m/z): found 350.9225 ([M+H]+, C11H13Br2O3 ;
+
calc. 350.9226).
TOF, m/z): found 271.0329 ([M+H]+, C12H16BrO2 ; calc.
271.0328).
2‑Bromo‑1‑(4‑(bromomethyl)phenyl)propan‑1‑one 7a.
2‑Bromo‑1‑(4‑(bromomethyl)phenyl)‑2‑methylpro‑
5a (0.044 g, 0.3 mmol), NBS (0.059 g, 0.33 mmol). Prepara-
tive TLC (Rf =0.51, CH2Cl2/petroleum ether 1:3). Colorless
solid (0.010 g, 20%). M.p. 80–83 °C. IR (neat): ν 2928,
1675, 1604, 1438, 1417, 1345, 1235, 1205, 1155, 1093, 993,
pan‑1‑one 10a.
8a (0.049 g, 0.3 mmol), NBS (0.059 g, 0.33 mmol). Pre-
parative TLC (Rf =0.48, CH2Cl2/petroleum ether 1:3). Yel-
lowish solid (0.012 g, 23%). M.p. 36–38 °C. IR (neat): ν
1
−1
948, 857, 823, 767, 723, 702, 635 cm . H NMR (500 MHz,
1 3

Chemical Papers
2979, 1668, 1603, 1451, 1411, 1388, 1264, 1230, 1203,
134.8, 136.5, 155.9, 193.9. HRMS (ESI-TOF, m/z): found
+
319.0326 ([M+H]+, C16H16BrO2 ; calc. 319.0328).
−1
1163, 1102, 979, 887, 849, 820, 764, 713, 679, 606 cm .
1H NMR (500 MHz, CDCl3): δ 2.03 (s, 6H), 4.50 (s, 2H),
7.46 (d, J=8.4 Hz, 2H), 8.13 (d, J=8.4 Hz, 2H). 13C NMR
(125 MHz, CDCl3): δ 31.5, 32.1, 60.2, 128.8, 130.7, 134.6,
142.0, 196.1. HRMS (ESI-TOF, m/z): found 318.9329
([M+H]+, C11H13Br2O+; calc. 318.9328).
2‑Bromo‑2‑phenyl‑1‑(thiophen‑2‑yl)ethan‑1‑one 12d.
11d (0.303 g, 1.5 mmol), NBS (0.320 g, 1.8 mmol). Col-
umn chromatography on silica gel (Rf = 0.53, CH2Cl2/
hexane 1:2 → 2:1). Yellow solid (0.304 g, 72%). M.p.
36–39 °C. IR (neat): ν 3089, 1660, 1514, 1494, 1454,
1408, 1353, 1285, 1237, 1222, 1178, 1062, 948, 859, 719,
2‑Bromo‑1‑(3‑(bromomethyl)‑4‑methoxyphenyl)‑2‑methyl‑
propan‑1‑one 10d.
1
−1
691, 634 cm . H NMR (500 MHz, CDCl3): δ 6.20 (s,
1H), 7.11 (dd, J = 3.9, 4.8 Hz, 1H), 7.30–7.40 (m, 3H),
7.53–7.59 (m, 2H), 7.68 (dd, J=0.9, 4.8 Hz, 1H), 7.76 (dd,
J = 0.9, 3.9 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 51.4,
128.3, 129.0, 129.0, 129.2, 133.4, 135.2, 135.8, 140.6,
184.1. HRMS (ESI-TOF, m/z): found 280.9628 ([M + H]+,
C12H10BrOS+; calc. 280.9630).
8d (0.058 g, 0.3 mmol), NBS (0.059 g, 0.33 mmol). Pre-
parative TLC (Rf = 0.21, CH2Cl2/petroleum ether 1:5).
Colorless solid (0.011 g, 18%). M.p. 79–81 °C. IR (neat):
ν 2929, 1655, 1595, 1503, 1458, 1444, 1265, 1223, 1142,
−1
1105, 1034, 1018, 1001, 937, 916, 842, 819, 763, 617 cm .
1H NMR (500 MHz, CDCl3): δ 2.04 (s, 6H), 3.97 (s, 3H),
4.57 (s, 2H), 6.91 (d, J=8.8 Hz, 1H), 8.22 (d, J=2.3 Hz,
1H), 8.26 (dd, J = 2.3, 8.8 Hz, 1H). 13C NMR (125 MHz,
CDCl3): δ 28.1, 31.8, 55.9, 60.4, 110.0, 125.9, 126.8, 133.4,
133.6, 160.7, 194.5. HRMS (ESI-TOF, m/z): found 348.9432
2,2‑Dibromo‑2‑phenyl‑1‑(thiophen‑2‑yl)ethan‑1‑one 13d.
11d (0.303 g, 1.5 mmol), NBS (0.320 g, 1.8 mmol). Col-
umn chromatography on silica gel (Rf = 0.67, CH2Cl2/
hexane 1:2 → 2:1). Brownish solid (0.052 g, 16%). M.p.
65–69 °C. IR (neat): ν 3109, 2921, 1667, 1491, 1444,
1406, 1350, 1238, 1222, 1190, 1084, 1064, 961, 845,
+
([M+H]+, C12H15Br2O2 ; calc. 348.9433).
2‑Bromo‑1‑(4‑methoxyphenyl)‑2‑phenylethan‑1‑one 12b.
1
−1
801, 749, 722, 704, 689, 648 cm . H NMR (500 MHz,
CDCl3): δ 6.92 (dd, J = 4.0, 4.9 Hz, 1H), 7.30 (dd, J = 1.1,
4.0 Hz, 1H), 7.33–7.42 (m, 3H), 7.56 (dd, J = 1.1, 4.9 Hz,
1H), 7.66–7.71 (m, 2H). 13C NMR (125 MHz, CDCl3):
δ 68.4, 127.3, 127.8, 128.8, 129.8, 135.1, 136.1, 136.3,
140.7, 180.1. HRMS (ESI-TOF, m/z): found 358.8727
([M + H]+, C12H9Br2OS+; calc. 358.8735).
11b (0.068 g, 0.3 mmol), NBS (0.059 g, 0.33 mmol). Col-
umn chromatography on silica gel (Rf =0.47, CH2Cl2/petro-
leum ether 1:3→2:1). Pale yellowish solid (0.055 g, 60%).
M.p. 67–70 °C. IR (neat): ν 2928, 1671, 1601, 1571, 1508,
1452, 1422, 1357, 1312, 1264, 1217, 1173, 1027, 846, 824,
1
−1
774, 734, 688 cm . H NMR (500 MHz, CDCl3): δ 3.85 (s,
3H), 6.36 (s, 1H), 6.89–6.93 (m, 2H), 7.29–7.38 (m, 3H),
7.51–7.55 (m, 2H), 7.95–8.00 (m, 2H). 13C NMR (125 MHz,
CDCl3): δ 51.1, 55.5, 114.0, 126.9, 128.9, 129.0, 129.0,
131.5, 136.3, 163.9, 189.6. HRMS (ESI-TOF, m/z): found
2‑Bromo‑2,4‑diphenyl‑3‑oxobutanenitrile 15.
14 (0.071 g, 0.3 mmol), NBS (0.059 g, 0.33 mmol). Col-
umn chromatography on silica gel (Rf = 0.70, CH2Cl2/
petroleum ether 1:3 → 2:1). Yellowish oil (0.070 g, 75%).
IR (neat): ν 2923, 1731, 1495, 1449, 1320, 1031, 1002,
+
305.0165 ([M+H]+, C15H14BrO2 ; calc. 305.0172).
1
−1
2‑Bromo‑1‑(5‑methyl‑2‑methoxyphenyl)‑2‑phenyle‑
than‑1‑one 12c.
705, 691, 646 cm . H NMR (500 MHz, CDCl3): δ 3.99
(d, J = 16.7 Hz, 1H), 4.03 (d, J = 16.7 Hz, 1H), 7.01–7.06
(m, 2H), 7.22–7.29 (m, 3H), 7.43–7.48 (m, 3H), 7.62–7.68
(m, 2H). 13C NMR (125 MHz, CDCl3): δ 43.1, 54.1, 116.0,
127.5, 127.6, 128.6, 129.4, 129.5, 130.6, 131.3, 132.1,
190.9. HRMS (ESI-TOF, m/z): found 314.0173 ([M + H]+,
C16H13BrNO+; calc. 314.0175).
11c (0.120 g, 0.5 mmol), NBS (0.107 g, 0.6 mmol). Col-
umn chromatography on silica gel (Rf = 0.45, CH2Cl2/
hexane 1:2 → 2:1). Yellowish solid (0.100 g, 63%). M.p.
44–46 °C. IR (neat): ν 2943, 1676, 1607, 1579, 1495, 1453,
−1
1401, 1285, 1246, 1157, 1126, 1020, 810, 695, 626 cm .
1H NMR (300 MHz, CDCl3): δ 2.27 (s, 3H), 3.85 (s, 3H),
6.59 (s, 1H), 6.81 (d, J = 8.5 Hz, 1H), 7.21–7.36 (m, 4H),
7.44–7.53 (m, 3H). 13C NMR (75 MHz, CDCl3): δ 20.2,
55.1, 55.7, 111.5, 125.5, 128.6, 128.6, 129.4, 130.5, 131.9,
2‑Bromo‑2‑phenylacetonitrile 18.
16 (0.048 g, 0.3 mmol), NBS (0.059 g, 0.33 mmol). Pre-
parative TLC (Rf = 0.35, CH2Cl2/petroleum ether 1:3)
1 3

Chemical Papers
Yellowish oil (0.031 g, 53%). IR (neat): 2971, 1496, 1455,
131.6, 133.4, 157.7, 192.4. HRMS (ESI-TOF, m/z): found
1
+
356.9117 ([M+H]+, C13H11Br2O2 ; calc. 356.9120).
−1
1188, 1138, 971, 817, 763, 690, 653, 621 cm . H NMR
(300 MHz, CDCl3): δ 5.49 (s, 1H), 7.39–7.48 (m, 3H),
7.52–7.60 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 27.4,
116.2, 127.8, 129.5, 130.3, 133.5.
Results and discussion
The ketones under investigation were arranged into the
groups of distinct alkyl substituents. First, we investigated
the regioselectivity of functionalization at differently
phenyl-functionalized model acetophenones 1a–f. Neat
ketones were reacted with NBS under stirring and irradi-
ated using an 8-W energy-saving light bulb at 27 °C. The
results are summarized in Table 1.
1‑(3‑bromo‑4‑methoxynaphthalen‑1‑yl)ethanone 21a.
19a (0.200 g, 1.0 mmol), NBS (0.356 g, 2.0 mmol). Col-
umn chromatography on silica gel (Rf = 0.24, CH2Cl2/
hexane 1:2 → 2:1). Brownish solid (0.008 g, 3%). M.p.
36–39 °C. IR (neat): ν 2940, 2848, 1663, 1568, 1501,
1401, 1352, 1275, 1229, 1134, 1073, 1008, 974, 835,
All substrates 1a–f responded to the above reac-
tion conditions in the same way, mainly affording
α-bromoacetophenones 2a–f, which were accompanied
by α,α-dibrominated products 4a–f. The selectivity was
poorer in the cases of 4’-methylacetophenone 1a and
4’-ethylacetophenone 1b, where α-bromination was
accompanied with benzylic bromination of the corre-
sponding alkyl (Me and Et) group, resulting in a small
amount of 3a and 3b, respectively (entries 1 and 2).
Surprisingly, selective benzylic bromination of 4’-meth-
ylacetophenone 1a into 4’-bromomethylacetophenone took
place with NBS in solvent-free reaction under concentrated
solar radiation (Deshpande et al. 2015). A comparison of
the photochemical functionalization of 4’-methylaceto-
phenone 1a with NBS under diferent reaction conditions
revealed interesting features. On water, 4’-bromomethy-
lacetophenone was the only product formed (Podgoršek
et al. 2009), whereas the treatment of 1a with NBS/SiCl4
in MeCN furnished the compound 3a as the sole prod-
uct (Salama and Novák 2011). Conversely, compound
1a was selectively α-brominated using NBS/PTSA under
ultrasound irradiation in methanol (Adhikari and Samant,
2002). In contrast to the straight-chain functionalized
derivatives, at the branched isopropyl 1c and cyclohexyl
1d acetophenones only α-bromination took place with no
benzylic bromination observed (entries 4 and 5). Increas-
ing the complexity of the substrate with additional reactive
sites, e.g., in 3’-methyl-4’-methoxyacetophenone 1e and
3’,5’-dimethyl-4’-methoxyacetophenone 1f, did not dimin-
ish the reaction selectivity, furnishing solely α-brominated
ketones 2e/4e and 2f/4f, respectively (entries 6 and 8).
Conducting the reactions with 1b and 1e in the presence
of a radical scavenger TEMPO (2,2,6,6-tetramethylpiperi-
din-1-yloxy) strongly infuenced the selectivity outcome.
As indicated in entries 3 and 7, benzylic bromination and
introduction of the second bromine atom to the α-position
were completely suppressed; hence, the only products
formed were 2b and 2e, respectively. Transformation of
1f did not take place in the absence of light (entry 9).
1
−1
759, 712, 675, 627 cm . H NMR (300 MHz, CDCl3):
δ 2.72 (s, 3H), 4.05 (s, 3H), 7.55–7.68 (m, 2H), 8.07 (s,
1H), 8.16–8.21 (m, 1H), 8.74–8.80 (m, 1H). 13C NMR
(125 MHz, CDCl3): δ 29.7, 61.7, 110.8, 122.3, 126.6,
127.3, 128.6, 129.6, 131.1, 132.8, 133.6, 156.9, 199.6.
HRMS (ESI-TOF, m/z): found 279.0013 ([M + H]+,
C13H12BrO2+; calc. 279.0015).
(3‑Bromo‑4‑methoxynaphthalen‑1‑yl)(phenyl)methanone
21c.
19c (0.079 g, 0.3 mmol), NBS (0.117 g, 0.66 mmol). Col-
umn chromatography on silica gel (Rf = 0.67, CH2Cl2/
petroleum ether 1:3→2:1). Yellowish solid (0.101 g, 99%).
M.p. 81–84 °C. IR (neat): ν 2922, 1649, 1567, 1501, 1448,
1372, 1270, 1243, 1152, 1070, 1054, 1022, 963, 863, 832,
1
−1
763, 710, 693, 670, 656, 613 cm . H NMR (500 MHz,
CDCl3): δ 4.08 (s, 3H), 7.45–7.51 (m, 2H), 7.51–7.56 (m,
1H), 7.57–7.65 (m, 2H), 7.71 (s, 1H), 7.84–7.89 (m, 2H),
8.08 (d, J=8.5 Hz, 1H), 8.22 (d, J=8.4 Hz, 1H). 13C NMR
(125 MHz, CDCl3): δ 61.7, 111.1, 122.4, 126.2, 127.4,
127.8, 128.6, 129.4, 130.4, 131.8, 132.1, 133.5, 133.9,
137.9, 155.6, 196.1. HRMS (ESI-TOF, m/z): found 341.0170
+
([M+H]+, C18H14BrO2 ; calc. 341.0172).
2‑Bromo‑1‑(3‑bromo‑4‑methoxynaphthalen‑1‑yl)ethanone
22a.
19a (0.200 g, 1.0 mmol), NBS (0.356 g, 2.0 mmol). Col-
umn chromatography on silica gel (Rf =0.33, CH2Cl2/hexane
1:2→2:1). Brownish solid (0.007 g, 2%). M.p. 64–69 °C. IR
(neat): ν 2934, 1686, 1566, 1503, 1373, 1265, 1213, 1165,
1124, 1089, 1074, 973, 908, 860, 836, 789, 761, 718, 701,
1
−1
680, 639 cm . H NMR (500 MHz, CDCl3): δ 4.07 (s, 3H),
4.53 (s, 2H), 7.60–7.70 (m, 2H), 8.07 (s, 1H), 8.19–8.23 (m,
1H), 8.62–8.67 (m, 1H). 13C NMR (125 MHz, CDCl3): δ
33.3, 61.8, 110.6, 122.5, 126.3, 127.7, 129.0, 129.7, 129.8,
1 3

Chemical Papers
Table 1 Transformation of neat substituted acetophenones 1a–f with NBS under visible-light irradiation
aSubstrate 1 (0.3 mmol), NBS (0.33 mmol), stirring, 8-W energy-saving light bulb, reaction temperature 27 °C
1
bConversions and relative distribution of products determined by H NMR spectroscopy of the crude reaction mixtures; values in parentheses
refer to isolated yields
cTEMPO (0.3 equiv.) was added
dProducts not isolated
Next, the selectivity of photo-transformations of model
aryl-substituted propiophenones 5 with NBS under SFRC
was examined. As with acetophenones 1, α-bromination
was the main reaction pathway, but in this case no α,α-
dibrominated products could be detected. Transformations
of most of the propiophenones exhibited a somewhat dif-
ferent selectivity compared to acetophenones. The results
are summarized in Table 2.
TEMPO was completely suppressed, and only α-bromination
could be detected with low conversion into 6a (entry 2). This
might indicate that the main reaction channels are of a radi-
cal nature. The reaction of 5a did not occur in the dark (entry
3). Transformation of 4’-methoxypropiophenone 5b gave the
corresponding α-bromoketone 6b as the main product. To
some extent, this was further brominated at the aromatic ring
also yielding a minor product 7b (entry 4). The sulfur ana-
logue, 4’-methylthiopropiophenone 5c, exhibited the highest
selectivity with only the α-carbon atom being brominated,
producing 6c (entry 5). Unexpectedly, the methylthio group
did not afect the type of functionalization as no aromatic
Functionalization of 4’-methylpropiophenone 5a yielded
α-brominated ketone 6a as the main product, accompanied
with a product of mixed α- and benzylic bromination 7a
(entry 1). Benzylic bromination of 5a in the presence of
1 3

Chemical Papers
Table 2 Regioselectivity of functionalization of neat substituted propiophenones with NBS under visible light
aSubstrate 5 (0.3 mmol), NBS (0.33 mmol), stirring, 8-W energy-saving light bulb, reaction temperature 27 °C
1
bConversions and relative distribution of products determined by H NMR spectroscopy of the crude reaction mixtures; values in parentheses
refer to isolated yields
cTEMPO (0.3 equiv.) was added
dKetone (1.0 mmol), NBS (1.5 mmol)
eProducts not isolated
substitution took place. The sulfur atom, being itself sen-
sitive to oxidation (Ali et al. 2006), remained unchanged.
The reaction of 2’-methoxy-5’-methylpropiophenone 5d,
which contained at least three potential reactive sites, gave
the related α-bromoketone 6d as the main product as well
as an additional side-chain brominated minor product 7d
(entry 6). Functionalization of 3’,4’-dimethoxypropiophe-
none 5e yielded α- and ring brominated 6e as the main
product, accompanied by 10% of α-bromoketone 7e (entry
7). Interestingly, no reaction took place in the presence of
TEMPO to 5e (entry 8). It appears that aromatic substitu-
tion of 5e takes place via a radical pathway. Reactions of
α-bromination of acetophenones and propiophenones in the
presence of TEMPO suggest involvement of electrophilic
and radical reaction pathways without clear boundary.
Subsequently, we selected model isobutyrophenones (aryl
isopropyl ketones) (Table 3).
bromination (Table 1, entries 4 and 5). In this step, the reac-
tivity of model isopropyl ketones was examined. The gen-
eral feature of ketones 8 was that, regardless of the nature
of the substituents under the studied reaction conditions,
α-bromoketones 9 were formed as the main products. Func-
tionalization of 4’-methylbutyrophenone 8a in addition
to the α-brominated ketone 9a also leads to the formation
of benzyl bromide 10a (entry 1). The reaction of 8a was
completely suppressed in the presence of TEMPO (entry 2)
as well as in the dark (entry 3). Reaction of 2’,4’-dimeth-
ylisobutyrophenone 8b, although being similar to 8a, did
not result in benzylic bromination, but the only product
formed was α-bromoketone 9b (entry 4). Transformation
of 4’-methoxyisobutyrophenone 8c exclusively produced
α-bromoketone 9c with no ring substitution noted (entry 5).
The reaction of 3’-methyl-4’-methoxybutyrophenone 8d
furnished a mixture of α-bromoketone 9d and benzyl bro-
mide 10d (entry 6). The addition of TEMPO to the reaction
mixture resulted in the recovery of the starting material 8d
In the group of acetophenones 1, the isopropyl and
cyclohexyl moieties in 1c and 1d did not undergo benzylic
1 3

Chemical Papers
Table 3 Regioselectivity of functionalization of neat substituted isobutyrophenones with NBS under visible light
aSubstrate 8 (0.3 mmol), NBS (0.33 mmol), stirring, 8-W energy-saving light bulb, reaction temperature 27 °C
1
bConversions and relative distribution of products determined by H NMR spectroscopy of the crude reaction mixtures; values in parentheses
refer to isolated yields
cTEMPO (0.3 equiv.) was added
dKetone (1.0 mmol), NBS (1.5 mmol)
(entry 7). In contrast to acetophenones and propiophenones,
the results of functionalization of isobutyrophenone suggest
that α-bromination proceeds exclusively by a radical mecha-
nism. This suggests that functionalization under solvent-free
conditions might depend on substrate structure, reminiscent
of radical α-bromination of highly substituted ketones with
bromine in the presence of 1,2-epoxycyclohexane under
photochemical conditions (Caló et al. 1977). Photochemical
α-bromination of ketones with NBS under UV–Vis irradia-
tion in diethyl ether is believed to follow a radical pathway
(Arbuj et al. 2007).
TEMPO completely stopped any transformation for 11a and
11d (entries 2 and 7), and no reaction took place for 11c in
the dark (entry 5). Functionalization of benzyl ketones in
the presence of TEMPO indicates that α-bromination might
proceed via radical pathway.
To examine the efect of the structure at the carbonyl
group on the reactivity of transformations under the applied
reaction conditions, two substrates, 14 and 16, with an addi-
tional electron-withdrawing nitrile group bonded to one of
the α-carbon atoms, were selected (Table 5).
Clearly, this triple activation in 14 and 16 had a strong
influence on regioselectivity and the reaction afforded
exclusively products 15 and 17, respectively (entries 1 and
3). Both reactions of 14 and 16 occurred even in the dark
(entries 2 and 4). When purifying the product 17 by means
of column chromatography, we observed an interesting phe-
nomenon, in which the acetyl group was partly cleaved on
the column and a mixture of 17 and 18 was eluted. Attempts
to separate these two compounds by a preparative thin-layer
chromatography resulted in complete deacetylation of 17
into product 18.
In the next step, we explored the reactivity of the selected
model benzyl ketones 11 (Table 4).
The highest regioselectivity was observed for this group,
with all substrates being brominated at the carbonyl car-
bon atom. This outcome was anticipated, because the site
of functionalization was an α-carbonyl and a benzylic posi-
tion at the same time. The presence of either methyl group
11a, methoxy group 11b or both 11c in the substrate did
not infuence the selectivity (entries 1, 3 and 4). Also, for
the substrate with a sensitive thiophene ring like in 11d,
only α-bromination into 12d was noticed, even though some
α,α-dibrominated product 13d was formed as well (entry 6).
Finally, the reactivity of naphthyl ketones was examined
(Table 6). The most interesting and unexpected result was
1 3

Chemical Papers
Table 4 Regioselectivity of functionalization of neat substituted benzyl ketones with NBS under visible light
aSubstrate 11 (0.3 mmol), NBS (0.33 mmol), stirring, 8-W energy-saving light bulb, reaction temperature 27 °C
1
bConversions and relative distribution of products determined by H NMR spectroscopy of the crude reaction mixtures; values in parentheses
refer to isolated yields
cTEMPO (0.3 equiv.) was added
dKetone (0.5 mmol), NBS (0.6 mmol)
eKetone (1.5 mmol), NBS (1.8 mmol)
Table 5 Regioselectivity of functionalization of neat substituted α-cyanoketones with NBS under visible light
aSubstrate 14/16 (0.3 mmol), NBS (0.33 mmol), stirring, 8-W energy-saving light bulb, reaction temperature 27 °C
1
bConversions and relative distribution of products determined by H NMR spectroscopy of the crude reaction mixtures; values in parentheses
refer to isolated yields
cOnly 18 isolated after column and preparative chromatography
dProducts not isolated
observed by irradiating (4-methoxynaphthyl) methyl ketone
19a with 2.2 equiv. of NBS under SFRC.
ketones on potential bromodeacylation. The fact that a simi-
lar distribution of the products was found for (4-methox-
ynaphthyl) ethyl ketone 19b (entry 4) indicates that the ipso-
substitution under these conditions could be more general.
Although the illumination of (4-methoxynaphthyl) benzyl
ketone resulted in a complex mixture of products, a signif-
cant amount of 20 was found in the crude reaction mixture,
indicating that bromodeacylation occurs with NBS under
Instead of the anticipated bromination at the alkyl side
chain, the main reaction pathway was ipso-substitution of
the acetyl group by a bromine atom alongside with aromatic
and α-carbonyl bromination as minor pathways (entry 1).
This observation stimulated us to examine the infuence
of the acyl moiety structure of (4-methoxynaphthyl) alkyl
1 3

Chemical Papers
Table 6 Regioselectivity of functionalization of neat substituted naphthyl ketones with NBS under visible light
aSubstrate 19 (0.3 mmol), NBS (0.66 mmol), stirring, 8-W energy-saving light bulb, reaction temperature 27 °C
1
bConversions and relative distribution of products determined by H NMR spectroscopy of the crude reaction mixtures; values in parentheses
refer to isolated yields
cTEMPO (0.3 equiv.) was added
dSubstrate 23 (0.3 mmol), NBS (0.33 mmol)
eIncomplete conversion, a complex reaction mixture
fProducts not isolated
SFRC with this substrate as well. To test the hypothesis that
an enolizable carbonyl group must be present for the ipso-
substitution, the non-enolizable (4-methoxynaphthalen-1-yl)
(phenyl)methanone 19c was subjected to the same reaction
conditions. The reaction exclusively furnished the ring-bro-
minated product 21c with no deacylation observed (entry
5). Interestingly, ipso-substitution was also noticed in the
case of the considerably electron-rich aryl ketone 2’-methyl-
4’,5’-dimethoxyacetophenone 23, in which the main bromo-
deacylated product 24 was accompanied by a small amount
of α-bromoketone 25 (entry 8). Bromodeacylation is rather
a rare process, known to take place with molecular bromine
in a solution (Beirne et al. 1970). The addition of TEMPO
to the reaction mixture resulted in diferent efects for dif-
ferent substrates. While inhibiting α-carbonyl bromination,
it had no efect on ipso- and ring substitution at 19a and
19c (entries 2 and 6). In contrast, TEMPO completely sup-
pressed all transformations of the compound 23 (entry 9).
Selectivity of the transformation of 19a in the dark was
decreased considerably resulting in a complex mixture of
products (entry 3), while no reaction took place with 19c in
the absence of light (entry 7).
Some further experiments were carried out in order to
shed light on mechanism of bromodeacylation. 4-Meth-
oxy-1-acetonaphthone 19a was reacted as a model sub-
strate under diferent reaction conditions with NBS and
bromine. Transformation of 19a with NBS/NH4OAc in
diethyl ether (Tanemura et al. 2004) led to 2-bromo-1-(4-
methoxynaphthalen-1-yl)ethan-1-one with 35% conver-
sion. Reaction of 19a with NBS/NH4NO3 in acetonitrile
(Tanemura et al. 2003) furnished a complex mixture
of ring-brominated products and a small proportion of
1 3

Chemical Papers
bromodeacylated product 20. Functionalization of 19a
with bromine in acetic acid furnished 2-bromo-1-(4-meth-
oxynaphthalen-1-yl)ethan-1-one with 65% conversion.
This reaction is assumed to take place in an electrophilic
fashion via enol form of 19a. The system NBS/pTSA in
DCM (Pravst et al. 2008; Vyas et al. 2016) expectedly
furnished 2-bromo-1-(4-methoxynaphthalen-1-yl)ethan-1-
one with 80% conversion. It can be concluded that electro-
philic functionalization of α-carbonyl position takes place
in the present of an acid (Br2/AcOH and NBS/pTSA in
DCM). The system NBS/NH4NO3 in acetonitrile led to the
expected electrophilic ring functionalization; in addition, a
minor portion of ipso-product 20 was observed. Reactions
in the presence of TEMPO suggest that the ring function-
alization of 19a might proceed via electrophilic and radi-
cal reaction pathways, while formation of 20 is supposed
to be attributed to a diferent reaction channel—potentially
a radical ion reaction pathway (Fasani et al. 1994).
reaction pathways of these sensitive compounds in reac-
tions with NBS under solvent-free reaction conditions.
Supplementary Information The online version contains supplemen-
tary material available at https://doi.org/10.1007/s11696-021-01711-x.
Acknowledgements The authors acknowledge the fnancial support
of the Slovenian Research Agency (Research Core Funding Grant
P1-0230) and Projects J1-8147 and J1-9166. The authors thank Dr.
Damijana Urankar for HRMS at the Centre for Research Infrastructure
at the Faculty of Chemistry and Chemical Technology (IC UL FCCT).
Open Access This article is licensed under a Creative Commons Attri-
bution 4.0 International License, which permits use, sharing, adapta-
tion, distribution and reproduction in any medium or format, as long
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Conclusions
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