Halogenation of ketones with N-halosuccinimides under solvent-free reaction conditions

Article abstract of DOI:10.1016/j.tet.2008.03.048

Several aryl substituted ketones, cyclic ketones, 1,3-diketones and a β-ketoamide were halogenated with N-halosuccinimides under solvent-free reaction conditions (SFRC) at various temperatures (20-80 °C), whereas less enolized ketones required the presence of an acid catalyst (p-toluenesulfonic acid, PTSA). Bromination of substituted acetophenones obeys first order kinetics v=k_Br[ketone] and the following correlation with the keto-enol equilibrium constant: log k_Br=0.3pK_E+C₁, less enolized substrates being more reactive; the moderate positive charge developed in the rate determining step was confirmed by the Hammett correlation (ρ=-0.5). On the other hand, in cyclic ketones an opposite relation was observed: log k_Br=-0.6pK_E+C₂, indicating higher reactivity of substrates with higher enolization constant (K_E). The important role of the nature of the solvent (MeCN, MeOH) in preorganization of the ketone-NBS-PTSA mixture prior to SFRC bromination was found.

Full text of DOI:10.1016/j.tet.2008.03.048

Tetrahedron 64 (2008) 5191–5199
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Halogenation of ketones with N-halosuccinimides under
solvent-free reaction conditions
,
,
*
Igor Pravst a, Marko Zupan a b, Stojan Stavber b
a
ˇ
ˇ
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, Ljubljana, Slovenia
Laboratory for Organic and Bioorganic Chemistry, ‘Jozef Stefan’ Institute, Jamova 39, Ljubljana, Slovenia
b
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Several aryl substituted ketones, cyclic ketones, 1,3-diketones and a b-ketoamide were halogenated with
N-halosuccinimides under solvent-free reaction conditions (SFRC) at various temperatures (20–80 ꢀC),
whereas less enolized ketones required the presence of an acid catalyst (p-toluenesulfonic acid, PTSA).
Bromination of substituted acetophenones obeys first order kinetics v¼kBr[ketone] and the following
correlation with the keto–enol equilibrium constant: log kBr¼0.3pKEþC1, less enolized substrates being
more reactive; the moderate positive charge developed in the rate determining step was confirmed by
the Hammett correlation (r¼ꢁ0.5). On the other hand, in cyclic ketones an opposite relation was ob-
served: log kBr¼ꢁ0.6pKEþC2, indicating higher reactivity of substrates with higher enolization constant
(KE). The important role of the nature of the solvent (MeCN, MeOH) in preorganization of the ketone–
NBS–PTSA mixture prior to SFRC bromination was found.
Received 17 December 2007
Received in revised form 28 February 2008
Accepted 13 March 2008
Available online 15 March 2008
Keywords:
Solvent-free reaction conditions
Halogenation
N-Halosuccinimides
Ketones
Neat
Regioselectivity
Kinetics
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
methoxy and carbonyl group in p-methoxy acetophenone makes
the phenyl ring and the molecule as a whole very sensitive to re-
Demands for sustainable and ecologically friendly organic syn-
theses2 are stimulating the search for alternatives to the use of
organic solvents in synthetic reactions. Performing reactions under
solvent-free reaction conditions (SFRC) is an important and in-
teresting alternative, but reaction pathways, as well as the products
formed, can be modified significantly.3,4
N-Halosuccinimides represent an important class of haloge-
nating reagents,5 among which N-bromosuccinimide (NBS) is
widely used; transformations can be modulated with various re-
action conditions (catalysts,6 solvents,7 mediators8 and SFRC9). Aryl
substituted ketones, possessing two potential donor sites, are very
sensitive model compounds and the important role of the solvent
on the regioselectivity of electrophilic functionalization was al-
ready reported.5,10 Two reaction pathways have been observed in
bromination of acetophenones: a positive Hammett r value was
observed in functionalization with deprotonation and development
of a negative charge at the a position as the dominant process
(Scheme 1, case B), while a negative r value was observed in acid-
catalyzed functionalization with the development of positive
charge (case A).10 The conjugation of electrons between the
action conditions and an excellent model substrate,11 resulting in
different regioselectivity of functionalization, i.e., ring versus side
chain substitution. The important role of the solvent on the regio-
selectivity of p-methoxy acetophenone has been demonstrated
several times in various halogenations.1,12
We now wish to report our investigations of the effect of the
structure of N-halosuccinimides, the influence of catalyst, reaction
temperature and the aggregate state of the substrates on the ha-
logenation of ketones under SFRC, a continuation of our pre-
liminary communication.1 Because of the lack of quantitative
information on transformations under SFRC, the effect of ketone
structure and reaction conditions on bromination was evaluated
kinetically, while the Hammett correlation offered further insight
into the nature of side chain bromination (Scheme 1).
2. Results and discussion
Acetophenone was used as a target molecule in evaluation of
various halogenating agents with respect to mono versus dis-
ubstitution, oxidation or ring functionalization in several stud-
ies.5,10 Bromination with NBS depends on the catalyst used and it
has also been confirmed recently that photo initiated trans-
formation in diethyl ether gave a high yield of mono brominated
products.13
* Corresponding author. Tel.: þ386 1 477 3660; fax: þ386 1 2519 385.
E-mail addresses: igor.pravst@ijs.si (I. Pravst), marko.zupan@fkkt.uni-lj.si
(M. Zupan), stojan.stavber@ijs.si (S. Stavber).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.048

5192
I. Pravst et al. / Tetrahedron 64 (2008) 5191–5199
Table 2
O
SFRC halogenation of 2-acetylcyclohexanone (4, liquid) and 3-oxo-3,N-diphenyl-
propionamide (6, solid) with N-halosuccinimides
R2
R1
X
Reagenta
Product
Yield [%]
X=Cl, Br, I
Substrate
Solvent-Free
O
O
O
O
SFRC
NCS
NBS
NIS
5a (X¼Cl)
5b (X¼Br)
5c (X¼I)
95
98
72
X
Reaction Cond.
4
6
X
N
O
O
A-H
O
O
NCS
NBS
NIS
7a (X¼Cl)
7b (X¼Br)
7c (X¼I)
67
85
83
O
O
Ph
NHPh
Ph
NHPh
X
O
a
Reaction cond.: 1 mmol of substrate; 1 mmol of NXS; SFRC, 20 ꢀC; reaction time:
solid
R2
R1
5a,c and 7, 3 h; 5b, 1 h.
liquid
H
required for transformation of liquid 2-acetylcyclohexanone (4)
and after 1 h at room temperature, brominated derivative 5b was
formed in quantitative yield (Table 2). Iodination and chlorination
also proceeded without the presence of a catalyst, while a longer
reaction time (3 h) was required for complete conversion with an
excellent yield of chlorinated derivative 5a. Iodination did not
proceed quantitatively and product 5c was isolated in 72% yield
after column chromatography, but started to decompose immedi-
ately after the isolation process. In order to determine the selec-
tivity of the process (mono vs dihalogenation), SFRC halogenations
were investigated on solid 3-oxo-3,N-diphenylpropionamide (6).
No catalyst was needed to achieve selective monohalogenation at
room temperature, despite the fact that the reaction mixtures
remained solid, while yields of isolated products are slightly lower
than in the case of diketone 4 with NCS and NBS, and higher for
iodinated product 7c (Table 2). The use of SFRC for halogenation of
ketones and diketones with N-halosuccinimides was shown to be
more selective than several published examples in which dihalo-
genation was usually enhanced by in-situ generation of acid or by
a higher degree of enolization of monohalosubstituted substrates in
solvents.14 It is interesting to mention the effect of reaction tem-
perature on the course of halogenation under SFRC (liquified re-
action mixture), since at higher temperature (60 ꢀC) selectivity was
lost and further halogenation took place.
δ+
H
H
δ−
δ−
A
O
A
O
2
R2
R
δ−
Ar
Ar
δ+
H
Hδ+
A: ρ < 0
B: ρ > 0
OH
R2
Ar
Scheme 1.
First, we studied the effect of the N-halosuccinimide (NXS)
structure on the halogenation of acetophenone (1) under SFRC.
Room temperature reaction in the absence of a catalyst was not
successful (entries 1, 3 and 5), while in the presence of 0.1 mmol of
p-toluenesulfonic acid (PTSA) immediate bromination was ob-
served with 95% conversion to 2b after 3 h (Table 1, entry 2). A
similar reaction with N-chlorosuccinimide (NCS) in the presence of
PTSA gave a much lower conversion after 3 h, but could be en-
hanced by prolonged reaction times and resulted in 84% conversion
after 24 h. However, lower selectivity was observed and mono-
chlorinated derivative 2a was accompanied by 6% of 2,2-dichloro-
1-phenylethanone-1-one (3a, entry 4). High conversion was also
observed for iodination with N-iodosuccinimide (NIS), where
monoiodo product 2c was formed selectively (entry 6).
The effect of the trifluoromethyl group and various hetero-
aromatic groups on the regioselectivity of halogenation of
1,3-diketones was investigated under SFRC (Table 3). Similar to
bromination with NBS,9f chlorination and iodination also proceed
selectively and only monohalogenation of the methylene group
was observed at room temperature in the absence of catalysts. It is
In contrast to acetophenones, b-diketones, b-keto esters and b-
keto amides have a higher degree of enolization, which is also
reflected in their halogenation under SFRC. No catalyst was
Table 3
SFRC halogenation of trifluoromethyl substituted 1,3-diketones with N-halo-
succinimides and water-based work-up
Table 1
The effect of reagent and catalyst on halofunctionalisationa of acetophenone (1)
O
O
O
HO OH
CF3
NXS
SFRC, 20 °C
O
O
O
R
CF3
R
X
X
X
NXS
SFRC
cat., 20 °C
+
8-10
11a-c: X=Cl
12a-c: X=Br
13a-c: X=I
X
2
3a: X=Cl
a: X=Cl
b: X=Br
c: X=I
1
Subs.
R
Reagenta
Reaction time [h]
Prod.
Yield [%]
NCS
NBS
NIS
0.2
0.2
2
11a
12a
13a
71
91
86
Entry
NXS
NBS
Cat.
T [h]
Conv. [%]
Selectivity 2:3
8
1
2
d
24
3
19
95
1:0
1:0
PTSA
NCS
NBS
NIS
1
0.2
1
11b
12b
13b
74
86
87
O
3
4
NCS
NIS
d
24
24
d
9
PTSA
90
15:1
5
6
d
24
24
d
NCS
NBS
NIS
0.2
0.2
0.2
11c
12c
13c
80
90
79
S
PTSA
81
1:0
10
a
Reaction conditions: 1 mmol of ketone 1, 1 mmol of NXS, cat. (0.1 mmol of PTSA),
a
conversion determined by NMR.
Reaction conditions: 1 mmol of substrate, 1 mmol of NXS.

I. Pravst et al. / Tetrahedron 64 (2008) 5191–5199
5193
O
O
O
O
NBS
C7H15
C7H15
Br C7H15
25a: 4-OMe
b: 3-OMe
+
cat., 20 °C
(OMe)n
Br
17b
(88%, a:b=1:2)
17a
16
c: 2-OMe
d: 2,4-(OMe)2
NBS SFRC
10% PTSA
O
O
Br
NBS
cis: 19a
trans: 19b
cat., 20 °C
O
O
(83%, a:b=1:1)
Br
18
MeO
O
O
Br
Br
MeO
OMe
21 (80%)
NBS
26a: 4-OMe
b: 3-OMe
c: 2-OMe
27d
cat., 80 °C
20
Scheme 2.
Scheme 4.
interesting that introduction of halogen atoms enhances water
addition to the carbonyl group next to the trifluoromethyl group in
comparison to the starting material, and stable hydrates
(1-substituted 2-halo-4,4,4-trifluoro-3,3-dihydroxybutan-1-ones,
11–13) were isolated in high yields after a water-based work-up.
Further, we examined the effect of ketone structure on bromi-
nation with NBS under SFRC. Aliphatic 5-nonanone (14) did not
react with NBS at room temperature, but 4-bromo-5-nonanone
(15) was formed in 93% yield when 10% of PTSA was present.
Acid-catalyzed SFRC bromination of 2-decanone (16) was not
regioselective, but a slight preference for substitution at the sec-
ondary carbon atom was observed and 1-bromo 17a and 3-bromo
17b were formed in 1:2 ratio (Scheme 2). No cis/trans preference for
substitution in solid 4-tert-butyl-cyclohexanone (18) was observed,
and cis-19a and trans-19b were formed in 1:1 ratio. Finally, on
changing the phenyl group to a more bulky adamantyl (20, solid),
bromination did not occur in the solid reaction mixture at room
temperature, though high conversion was achieved above the
melting point, at 80 ꢀC after 10 min.
and the presence of a methoxy group in benzocycloalcanones on
the regioselectivity of acid-catalyzed bromination under SFRC
(Scheme 3). At room temperature, both cyclopentanone 22a and
cyclohexanone 22c derivatives were effectively functionalized at
the side chain giving 23a and 23c in high yield, while introduction
of a methoxy group in the para position (22b,d) did not change the
regioselectivity, but both reaction mixtures had to be heated above
their melting point (80 ꢀC) for successful functionalization. Being
interested in the regioselectivity of further bromination, we found
that more rigorous conditions were necessary and substitution
took place only at the a position, forming dibrominated 24a–d in
good yields after 1 h at 80 ꢀC.
Since the methoxy group did not direct bromination to the ring
position, we were stimulated to investigate its effect in three iso-
mers of methoxy acetophenone (25a–c), which were all effectively
brominated on the side chain after 2 h at room temperature in the
presence of 10% PTSA (Scheme 4). Introduction of a second
methoxy group changed the regioselectivity and 2,4-dimethoxy
acetophenone (25d) was regioselectively transformed to 5-bromo
derivative 27d without the presence of PTSA after 24 h (88% con-
version), while the presence of PTSA did not change the regiose-
lectivity, but increased the reactivity (93% conversion after 2 h).
Further, we have examined the role of the aggregate state of
acetophenones and the amount of acid catalyst (PTSA) on the
course of bromination under SFRC. As evident from Figure 1, liquid
The influence of electron distribution between the oxygen
atoms in aromatic ketones with the methoxy group in the para
position to the carbonyl has already been demonstrated, the system
being very sensitive to reaction conditions, which finally resulted
in regioselective functionalization (ring vs side chain sub-
stitution).1,11,12 We studied the effect of aggregate state, ring size
O
22a: n=1, R=H
b: n=1, R=OMe
c: n=2, R=H
100
d: n=2, R=OMe
(CH2)n
O
R
80
NBS
cat.
SFRC
a, c: 20 °C
b, d: 80 °C
1
60
O
23a: n=1, R=H
b: n=1, R=OMe
c: n=2, R=H
Br
40
O
(CH2)n
R
R
d: n=2, R=OMe
25e
NBS
cat.
SFRC
80 °C
20
F3C
O
0
Br
24a: n=1, R=H
b: n=1, R=OMe
c: n=2, R=H
0
2
4
6
8
10
Br
mol% PTSA
(CH2)n
d: n=2, R=OMe
Figure 1. The effect of catalyst (PTSA) on the bromination of substituted acetophe-
nones with NBS under SFRC at 20 ꢀC (rt: 1, 3 h; 25e, 6 h).
Scheme 3.

5194
I. Pravst et al. / Tetrahedron 64 (2008) 5191–5199
Table 4
acetophenone (1) responded differently from the solid substrate
bearing an electron withdrawing group 25e (p-CF3), which was also
shown to be less reactive and required more catalyst. Based on
these results, 10% of PTSA was used for further halogenation to
achieve stable reaction condition and the best reproducibility.
Migration of molecules in a reaction mixture is a very important
process in SFRC transformations and attention must be paid to it
when a transformation is declared to be a solid state one.4b,15 It is
known that molecules are much more mobile in liquid reaction
mixtures, and this can be the case either with (1) liquid substrates,
(2) solid substrates forming liquid reaction mixtures due to for-
mation of a eutectic, or (3) due to formation of a liquid product (or
eutectic). We studied the effect of reaction temperature on the
bromination of solid 1,2-diphenylethanone (28). The reaction sys-
tem composed of three solid compounds remained solid when
triturated at room temperature and no reaction took place even
after 24 h, but fast bromination was observed at 80 ꢀC when the
reaction system becomes molten. Figure 2 demonstrates the effect
of reaction temperature on the course of bromination (conversions
after 8 min) and it is evident that effective functionalization took
place in the molten state.
In order to obtain some further insight into the bromination
process, we investigated the effect of the aggregate state of two
structurally similar ketones: solid indanone (22a) and liquid tet-
ralone (22c). As evident from Table 4, the liquid substrate was al-
most twice as reactive as the solid one (entries 1 and 9). Further, we
compared the reactivity of both substrates in two different solvents
(methanol and acetonitrile) and it is interesting that solid 22a was
less reactive in methanol than under SFRC (entry 2). Tetralone re-
activity was not affected (entry 10), but a further strong decrease of
reactivity was noted in acetonitrile (entry 12). Preorganization (PO)
of donor and acceptor molecules achieved in solution could have an
important influence on further reactivity in transformations under
SFRC.16 Being interested in this effect, we decided to preorganize
solid 22a and liquid 22c in two different solvents (methanol or
acetonitrile). PO was achieved by dissolving the ketone, NBS and
PTSA in the organic solvent, which was then evaporated under
reduced pressure at 20 ꢀC in 5 min and the reaction mixture was
then left for additional 25 min at 20 ꢀC. To obtain reproducible data,
it is very important that after the reaction time NBS was immedi-
ately quenched with NaHSO3.
The effect of ketone structure, aggregate state (solid a-indanone: 22a, liquid a-tet-
ralone: 22c, solid 1,2-diphenylethanone: 28) and reaction conditions on bromina-
tion with NBSa
Entry
Comp.
Conditions
Conv. [%]
1
2
3
4
5
6
7
8
22a
SFRCb
44
17
88
73
1
8
86
19
SOL–MeOHc
PO–MeOH–SFRCe
PO–MeOH–SFRCf
AD–MeOHd
SOL–MeCN
PO–MeCN–SFRC
PO–MeCN–SFRCf
9
22c
28
SFRC
SOL–MeOH
PO–MeOH–SFRC
SOL–MeCN
PO–MeCN–SFRC
PO–MeCN–SFRCf
72
70
88
5
91
20
10
11
12
13
14
15
16
17
18
SFRC
SOL–MeCN
PO–MeCN–SFRC
PO–MeCN–SFRCf
69
1
72
14
a
Ketone (0.5 mmol), NBS (0.5 mmol), PTSA (0.05 mmol), rt: 30 min, T: 20 ꢀC for
22a and 22c, 40 ꢀC for 28.
b
SFRC: solvent-free reaction conditions.
SOL: reactants dissolved in 2.5 mL of named solvent; quenched after 30 min.
AD: added 1.5 mmol of MeOH to reaction mixture and quenched after 5 min.
PO: preorganization of reactants in 2.5 mL of named solvent, solvent evaporated
c
d
e
(5 min), quenched after 25 min.
f
Evaporated in 5 min and quenched.
(entries 3, 7, 11, and 13). A superior effect was observed when the
reaction time was shortened to 5 min (including evaporation) and
transformation after PO in methanol was much more effective than
in acetonitrile (entries 4 and 8). It is interesting that almost the
same degrees of conversion were observed after 5 min for both
ketones when preorganized in acetonitrile (entries 8 and 14). To
clarify the high effect of PO in methanol on the transformation, an
additional experiment using a small amount of solvent (AD) was
performed, but only negligible conversion was observed after 5 min
(entry 5). It is interesting to compare this result with recently
reported observations, that a small amount of added solvent sig-
nificantly enhanced the transformation.17 Finally, we evaluated the
behaviour of solid diphenylethanone 28, which was unreactive at
room temperature, but bromination was achieved at 40 ꢀC (entry
15); this ketone was also unreactive in acetonitrile (entry 16). The
absence of a PO effect in acetonitrile was established (entry 17),
indicating the important role of the substrate structure on PO and
its potential further effect on SFRC transformations.
Both ketones were more reactive in the preorganized state, but
the increase in reactivity was much more pronounced for solid 22a
(entries 3 and 7). Conversions after 30 min did not reflect the in-
fluence of the solvent used for PO, in all cases being very high
80
Many transformations of organic substrates could be effectively
performed under SFRC, but only a very limited number of quanti-
tative investigations were published.3,4b Furthermore, to our
knowledge no kinetic investigations of brominations with NBS
under SFRC have yet been published. We first investigated the ki-
netics of bromination of substituted acetophenones (liquid 1, solid
25a and 25e) with NBS in the presence of 10% PTSA under SFRC. The
study was performed at 40 ꢀCdabove the melting point of all
substrates, and the progress of ketone consumption was monitored
by 1H NMR spectroscopy. Surprisingly a very good correlation
(R2>0.99) and reproducibility was found as evident from Figure 3,
in which the reactions followed simple first order kinetics
v¼kBr[ketone].
40
O
28
0
The p-methoxy derivative 25a proved to be more
ꢀC
20
30
40
50
T [°C]
60
70
80
(kBr(25a)40 ¼1.8ꢂ10ꢁ3 sꢁ1), and p-trifluoromethyl 25e less reactive
ꢀC
ꢀC
(kBr(25e)40 ¼0.6ꢂ10ꢁ3 sꢁ1
)
than acetophenone (kBr(1)40
¼
1.6ꢂ10ꢁ3 sꢁ1. Further, we verified whether the competitive reaction
Figure 2. The effect of reaction temperature on the bromination of 1,2-diphenyl-
ethanone (28, solid) with NBS under SFRC (cat.: 10% PTSA; rt: 8 min).
technique is applicable for SFRC transformations and the progress of

I. Pravst et al. / Tetrahedron 64 (2008) 5191–5199
5195
Table 5
0
-1
-2
Effect of reaction conditions on the reactivity of methoxy substituted acetophenones
with NBSa
rel
Subst.
Acetophenone
k
Br
MeCN, 60 ꢀ
C
SFRC, 20 ꢀ
C
H
1
1
3
1
2.5
1
25e (R: 4-CF3)
2-OMe
3-OMe
4-OMe
25c
25b
25a
1.5
0.8
1.2
a
Reaction in the presence of 10% PTSA, substr. conc: 0.2 M in MeCN.
of bromination of 22b with NBS (Table 4; MeCN: 5% conversion,
SFRC: 72% conversion after 30 min), therefore we examined the role
of the solvent on the progress of side chain bromination of three
isomeric methoxy substituted acetophenones (25a–c), comparing
the reactions under SFRC. As evident from Table 5, the pattern of
reactivity in acetonitrile is the same as under SFRC, but the effect of
the substituent is more pronounced when the methoxy group is
conjugated (ortho or para position) to the carbonyl group. In ace-
tonitrile, the 2-methoxy (25c) isomer is 3 times, and 4-methoxy
(R: 4-OMe) 25a
500 1000
1 (R: H)
2000
0
1500
t (s)
2500
Figure 3. The course of SFRC bromination of substituted acetophenones (1: C, 25a: B,
25e: ,) with NBS at 40 ꢀC (10% PTSA).
(25a) 2.5 times more reactive than acetophenone, while electron
rel
delocalization is less pronounced under SFRC (k 1.5 and 1.2, re-
Br
bromination of an equimolar mixture of acetophenone, 4-tri-
spectively). Introduction of a methoxy group at the meta position
(25b) does not influence the reactivity of the ketone in acetonitrile,
and only a small decrease was observed under SFRC.
fluoromethyl acetophenone and NBS with 10% PTSA was analyzed
rel
after complete consumption of NBS. The resulting k ¼0.5 is in good
Br
agreement with relative rates calculated from first the order rate
constants (kBr(1)/kBr(25e)¼0.4), and therefore we used this com-
petitive technique in further studies.
Finally, we have studied the effect of ring size and the phenyl
ring on the course of acid-catalyzed bromination of various cyclic
ketones with NBS under SFRC (Table 6), in which all of them were
converted to a-bromo derivatives. Cyclopentanone (30a) and
cycloheptanone (30c) are only slightly more reactive than aceto-
phenone (krel¼1.2 and 1.5) while cyclohexanone is 10 times more
reactive. Introduction of a phenyl ring enhances the reactivity of the
five membered ring and indanone (22a) is 2.3 times more reactive
than cyclopentanone, while tetralone (22c) is 4 times less reactive
than cyclohexanone. The effect of introduction of a phenyl group
into acetophenone was also examined and 1,2-diphenylethanone
(28) was determined to be 3.3 times less reactive.
The Hammett correlation has already been used for discrimi-
nation of the two processes involved in bromination of acetophe-
nones.10 As evident from Figure 4, a negative correlation constant
r¼ꢁ0.5 was found for acid-catalyzed bromination with NBS under
SFRC, indicating a moderate positive charge developed in the rate
determining step.
It is interesting to compare SFRC with reaction in organic sol-
vents. A significant increase in reaction rate was shown in the case
In order to understand the structural effects of ketones on
bromination under SFRC, we tried to correlate reaction constants
with pKa values18 and keto–enol equilibrium constants (pKE).19 No
relationship was found with pKa, but a good one with pKE, although
the dual behaviour of ketones is evident from Figure 5. In the
substituted acetophenone series (1, 25a,b,e,f), less enolized sub-
strates are more reactive: log kBr¼0.3pKEþC1. Functionalization
obeys first order kinetics v¼kBr[ketone] and is probably controlled
by the rate of enole formation (kE1), while further bromine addition
is much faster than enolization. This could also be supported by the
moderate positive charge, developed in the rate determining step,
0.4
ρ = -0.5
4-MeO
H
0.0
3-MeO
3-CF3
Table 6
Effect of ketone structure on rate of bromination with NBS under SFRC at 20 ꢀC (10%
PTSA)
4-CF3
-0.4
-0.30
0.00
0.30
0.60
rel
σ
Substrate
pKE
k
Br
O
R¼H
1
28
8.15
1.0
0.3
rel
R
Subst. acetophenone
pKE
kBr
σ
R¼Ph
4-OMe
H
25a
1
-0.27
0.00
0.12
0.43
0.54
8.87
8.15
8.15
7.78
7.57
1.2
1.0
0.8
0.6
0.5
O
n¼1
n¼2
n¼3
30a
30b
30c
8.00
6.64
8.10
1.2
10
1.5
3-OMe
3-CF3
4-CF3
25b
25f
25e
(CH2)n
O
n¼1
n¼2
22a
22c
7.48
2.8
2.5
Figure 4. Hammett correlation plot (log krBerl/s) for the bromination of substituted
acetophenones with NBS and 10% PTSA under SFRC at 20 ꢀC.
(CH2)n

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I. Pravst et al. / Tetrahedron 64 (2008) 5191–5199
1.2
0.8
0.4
0.0
-0.4
4. Experimental
log kBr = -0.6 pKE + C2
(cyclic ketones)
30b
4.1. General
Melting points were determined on a Bu¨chi 535 apparatus.
1H and 13C NMR spectra were recorded on a Varian INOVA 300
spectrometer at 300 MHz and 76 MHz, respectively. Chemical
shifts are reported in parts per million from TMS as the internal
22a
standard, using CDCl3 as
a
solvent. 19F NMR spectra were
30c
recorded on the same instrument at 285 MHz and chemical
shifts are reported in parts per million from CCl3F as the internal
standard. IR spectra were obtained with a Bio-Rad FTS 3000MX.
Standard KBr pellet procedures were used to obtain IR spectra of
solids, while a film of neat material was used to obtain IR
spectra of liquid products. Mass spectra were obtained on an
Autospec Q instrument under electron impact (EI) conditions at
70 eV. Elemental analyses were carried out on a Perkin Elmer
2400 Series II CHNS/O Analyzer. N-halosuccinimides (Merck)
and starting substrates (Sigma–Aldrich, Fluka) were used as re-
ceived, while p-toluenesulfonic acid (PTSA) was dried at 120 ꢀC
for 2 h and stored in a dry atmosphere. ACS grade solvents were
used.
25a
30a
1
log kBr = 0.3 pKE + C1
(acetophenones)
25b
25f
25e
6.5
7
7.5
8
8.5
9
pKE
Figure 5. Correlation between the enolization (pKE) of substituted acetophenones (C)
and cyclic ketones (B) and the rate of NBS bromination under SFRC (10% PTSA; data
from Table 4 and Fig. 4).
Isolated compounds were identified on the basis of spectro-
scopic data, elemental microanalysis and high resolution MS
spectrometry, while in the case of known compounds comparison
with literature data was made. In cases where spectroscopic data is
not stated, it is in accordance with previously reported data. All
conversions were determined using 1H or 19F NMR spectroscopy.
Crystallization or column chromatography were used for purifica-
tion of products where stated.
found in the Hammett correlation (r¼ꢁ0.5). The important role of
PTSA in activation of NBS and acetophenones must be taken into
account in functionalization under SFRC (Scheme 5). On the other
hand for cyclic ketones (22a, 30a–c), an opposite association was
observed: log kBr¼ꢁ0.6pKEþC2, indicating the higher reactivity of
substrates with a higher enolization constant (KE).
3. Conclusion
4.2. Halogenation of ketones (1, 14, 16, 18, 20, 22a–d, 25a–f, 28,
30a–c) under SFRC: general procedure
A
number of ketones were halogenated with N-halo-
succinimides and PTSA as acid catalyst under solvent-free reaction
conditions at various temperatures in molten reaction mixtures
(20–80 ꢀC), while halogenation of more enolized 1,3-diketones and
b-ketoamide also proceeded in the solid state and without catalyst.
The process was shown to be very selective and quicker than if
performed in organic solvents (acetonitrile, methanol). Aryl
substituted ketones are brominated on the side chain, even in the
case of introduction of a second bromine atom into a methoxy
substituted derivative and the bromination of substituted aceto-
phenones obeys first order kinetics v¼kBr[ketone]. For cyclic ke-
tones (22a, 30a–c), the correlation log kBr¼ꢁ0.6pKEþC2 was
determined, while acetophenones (1, 25a,b,e,f) show an opposite
correlation (log kBr¼0.3pKEþC1). The negative Hammett correlation
with r¼ꢁ0.5 indicates a moderate positive charge, developed in the
rate determining step.
Substrate (1 mmol) and N-halosuccinimide (NXS, 1 mmol) were
triturated together with p-toluenesulfonic acid (PTSA, 0.1 mmol) in
a porcelain mortar for 2–10 min. Most reaction mixtures melted
during reaction at 20 ꢀC, while mixtures with 20, 22b, 22d and 28
were heated to 80 ꢀC for 10 min to achieve melting. After the re-
action time (see Table 1 and compounds description), water (5 mL)
was added, followed by extraction with tert-butyl methyl ether or
CH2Cl2 (10 mL). The organic phase was washed with water
(10 mL), dried over Na2SO4 and solvent evaporated under reduced
pressure.
4.2.1. 2-Chloro-1-phenylethanone20,21 (2a)
Reaction performed with 2 mmol of ketone 1; crude product
(84% 2a, 6% 3a) was purified by column chromatography (SiO2:
CH2Cl2/hexane¼10:1, 70%), mp 54–55 ꢀC (lit.21 54–55 ꢀC).
4.2.2. 2,2-Dichloro-1-phenylethanone22 (3a)
X
X
X
E
k1
Isolated as a minor component in synthesis of 2a from crude
product (84% 2a, 6% 3a), purified by column chromatography (SiO2:
CH2Cl2/hexane¼10:1), oily product (4%).
E
k-1
O
CH3
O
CH3
HO
CH2
KE=k1E/k-1
E
4.2.3. 2-Bromo-1-phenylethanone23,24 (2b)
Crude product (95%) was crystallized, mp 47–48 ꢀC (from eth-
anol; lit.24 46–48 ꢀC).
Br
N
H
N
O
O
A
H
O
O
4.2.4. 2-Iodo-1-phenylethanone25 (2c)
Crude product (81%) additionally purified by column chroma-
tography (SiO2: CH2Cl2/hexane¼10:1), oily product.
X
kBr
E
kBr
Br
O
4.2.5. 4-Bromononan-5-one26 (15)
Scheme 5.
Reaction time: 2 h; oily product (93%).

I. Pravst et al. / Tetrahedron 64 (2008) 5191–5199
5197
4.2.6. 1-Bromodecan-2-one27 (17a) and 3-bromo-decan-2-
one28 (17b)
Reaction time: 4 h; crude reaction mixture (88%) composed of
17a and 17b in 1:2 ratio.
4.2.17. 2-Bromo-1-(4-trifluoromethylphenyl)-ethanone42 (26e)
Reaction time: 18 h; crude product (96%) was crystallized (54%),
mp 54–55 ꢀC (from ethanol; lit.42 53–54 ꢀC); 19F NMR (285 MHz;
CDCl3) d ꢁ63.8.
4.2.7. 2-Bromo-4-tert-butyl-cyclohexanone29;30 (cis: 19a,
trans: 19b)
Reaction time: 2 h; crude reaction mixture contained 83% of
both isomers in 1:1 ratio. 19a crystallized from pentane, mp 63–
65 ꢀC (lit.30 66 ꢀC).
4.2.18. 2-Bromo-1-(3-trifluoromethylphenyl)-ethanone43 (26f)
Reaction time: 18 h; crude product (89%) purified by column
chromatography (SiO2: CH2Cl2/hexane¼10:1), oily product (66%);
1H NMR (300 MHz; CDCl3) d 4.47 (s, 2H), 7.66 (dd, J¼7.8 Hz, 7.8 Hz,
1H), 7.87 (d, J¼7.8 Hz, 1H), 8.18 (d, J¼7.8 Hz, 1H), 8.24 (s, 1H); 19F
NMR (285 MHz; CDCl3) d ꢁ63.3.
4.2.8. 1-Adamantan-1-yl-2-bromoethanone31 (21)
Crude product (80%) was crystallized, mp 79–80 ꢀC (from eth-
anol; lit.31 78–79 ꢀC); 1H NMR (300 MHz; CDCl3) d 1.67–1.79 (m, 6H,
CH2), 1.88 (d, J¼2.7 Hz, 6H, CH2), 2.01–2.1 (s, 3H, CH), 4.16 (s, 2H,
CH2Br); 13C NMR (76 MHz; CDCl3) d 27.8, 31.8, 36.3, 38.5, 46.6, 205.5
(CO).
4.2.19. 2-Bromo-1,2-diphenylethanone44 (29)
Crude product (95%) was crystallized, mp 53–55 ꢀC (from eth-
anol; lit.44 55–56 ꢀC).
4.2.20. 2-Bromo-cyclopentanone45 (31a)
Reaction time: 2 h; crude product (86%) purified by column
chromatography (SiO2: CH2Cl2), oily product (84%); 1H NMR
(300 MHz; CDCl3) d 1.97–2.08 (m, 1H), 2.15–2.30 (m, 3H), 2.35–2.45
(m, 2H), 4.22–4.26 (m, 1H, CHBr). Decomposition observed after
a few days at 6 ꢀC.
4.2.9. 2-Bromoindan-1-one32 (23a)
Reaction time: 2 h; purified by column chromatography (SiO2:
CH2Cl2, 87%), mp 36–37 ꢀC (lit.32 37–38 ꢀC).
4.2.10. 2-Bromo-5-methoxyindan-1-one33 (23b)
Crude product (97%) was crystallized, mp 105–107 ꢀC (from
ethanol; lit.33 107.8–108.5 ꢀC); 1H NMR (300 MHz; CDCl3) d 3.37 (dd,
J¼18.2 Hz, 3.1 Hz, 1H), 3.79 (dd, J¼18.2 Hz, 7.5 Hz, 1H), 3.91 (s, 3H,
CH3O), 4.64 (dd, J¼3.1 Hz, 7.5 Hz, 1H, CHBr), 6.86 (d, J¼2.1 Hz, 1H,
ArH), 6.96 (dd, J¼2.1 Hz, 8.6 Hz, 1H, ArH), 7.77 (d, J¼8.6 Hz, 1H,
ArH); 13C NMR (76 MHz; CDCl3) d 38.0, 44.6, 55.8, 106.3 (ArC), 109.4
(ArCH), 116.3 (ArCH), 126.8 (ArCH), 154.1 (ArC), 166.3 (ArC), 197.6
(CO).
4.2.21. 2-Bromo-cyclohexanone23 (31b)
Reaction time: 2 h; crude product (96%) purified by column
chromatography (SiO2: CH2Cl2), oily product (93%).
4.2.22. 2-Bromo-cycloheptanone46 (31c)
Reaction time: 2 h; crude product (93%) purified by column
chromatography (SiO2: CH2Cl2), oily product (84%).
4.2.11. 2-Bromo-1-tetralone32,34 (23c)
4.3. Halogenation of 1,3-dicarbonyl compounds (4, 6, 8–10)
under SFRC: general procedure
Reaction time: 2 h; purified by column chromatography (SiO2:
CH2Cl2, 86%), mp 36–37 ꢀC (lit.32 38–39 ꢀC).
Substrate (1 mmol) and NXS (1 mmol) were triturated together
in a porcelain mortar for 5 min and left for 10–180 min at 20 ꢀC
(reaction times noted in Table 2 and Table 3). Water (4 mL) was
then added and the mixture triturated for 1 min. In the case of
halogenation of 4 (giving 5a–c) and chlorination of 9 (giving 11b),
this was followed by extraction with tert-butyl methyl ether or
CH2Cl2 (20 mL), washing the organic phase with water (10 mL),
drying over Na2SO4 and evaporation of solvent under reduced
pressure, while in other cases filtration of the solid product,
washing with water (20 mL) and drying in a desiccator under
reduced pressure was used.
4.2.12. 2-Bromo-6-methoxy-1-tetralone35 (23d)
Crude product (97%) was crystallized, mp 78–79 ꢀC (from eth-
anol; lit.35 79–81 ꢀC).
4.2.13. 2-Bromo-1-(4-methoxyphenyl)-ethanone36,37 (26a)
Reaction time: 2 h; crude product (73%) was crystallized, mp
68 ꢀC (from ethanol; lit.37 69–70 ꢀC).
4.2.14. 2-Bromo-1-(3-methoxyphenyl)-ethanone38 (26b)
Reaction time: 2 h; crude product (85%) was crystallized, mp
61–62 ꢀC (from ethanol; lit.38 55–57 ꢀC); 1H NMR (300 MHz; CDCl3)
d 3.86 (s, 3H, CH3O), 4.45 (s, 2H, CH2Br), 7.14 (ddd, J¼1.0, 2.5, 8.2 Hz,
1H), 7.39 (dd, J¼7.6, 8.2 Hz, 1H), 7.50 (dd, J¼1.5, 2.5 Hz, 1H), 7.54
(ddd, J¼7.6, 1.5, 1.0 Hz, 1H); 13C NMR (76 MHz; CDCl3) d 30.9 (CH3),
55.5 (CH2Br), 113.1 (ArCH),120.5 (ArCH),121.4 (ArCH),129.8 (ArCH),
135.3 (ArC), 160.0 (ArC), 191.1 (CO).
4.3.1. 2-Acetyl-2-chlorocyclohexanone47 (5a)
Oily product (95%).
4.3.2. 2-Acetyl-2-bromocyclohexanone9f (5b)
Oily product (98%); 1H NMR (300 MHz; CDCl3) d 1.72–1.91 (m,
2H),1.91–2.07 (m, 2H), 2.16–2.29 (m,1H), 2.29–2.42 (m,1H), 2.45 (s,
3H), 2.51–2.67 (m, 1H), 3.06–3.20 (m, 1H).
4.2.15. 2-Bromo-1-(2-methoxyphenyl)-ethanone39,40 (26c)
Reaction time: 2 h; crude product (91%) was crystallized, mp
42–43 ꢀC (from ethanol; lit.40 40–44 ꢀC).
4.3.3. 2-Acetyl-2-iodocyclohexanone (5c)
4.2.16. 1-(5-Bromo-2,4-dimethoxyphenyl)-ethanone41 (27d)
Reaction time: 2 h; crude product (93%) was crystallized (67%),
mp 138–139 ꢀC (from ethanol; lit.41 139–140 ꢀC); 1H NMR
(300 MHz; CDCl3) d 2.56 (s, 3H, CH3), 3.94 (s, 3H, CH3O), 3.96 (s, 3H,
CH3O), 6.45 (s, 1H, ArH), 8.03 (s, 1H, ArH); 13C NMR (76 MHz; CDCl3)
d 31.8 (CH3), 55.8 (CH3O), 56.4 (CH3O), 95.8 (ArCH), 102.7 (ArC),
121.4 (ArC), 135.1 (ArCH), 160.0 (ArC), 160.4 (ArC), 196.3 (CO); MS
m/z (EI, 70 eV) 260 (45%, Mþ), 258, 245, 243 (100%); high resolution
MS m/z 257.9902 (calcd for C10H11BrO3: 257.9892).
Purified by column chromatography (SiO2: CH2Cl2), oily product
(72%); 1H NMR (300 MHz; CDCl3) d 1.78–2.01 (m, 4H), 2.24–2.52 (m,
3H), 2.56 (s, 3H), 3.22–3.35 (m, 1H); 13C NMR (76 MHz; CDCl3)
d 23.9, 27.1, 27.4, 38.3, 40.4, 59.4, 200.7 (CO), 203.2 (CO); IR
nmax(KBr)/cmꢁ11694,1431,1366,1224,1177,1115,1065, 965; MS m/z
(EI, 70 eV) 266 (2%), 224 (100%), 111 (25%), 97 (45%), 55 (30%); high
resolution MS: m/z 265.9812 (calcd for C8H11IO2: 265.9804). The
product was not stable and started to decompose immediately after
chromatography.

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I. Pravst et al. / Tetrahedron 64 (2008) 5191–5199
4.3.4. 2-Chloro-3-oxo-3,N-diphenylpropionamide48 (7a)
Crude product was crystallized (67%), mp 118–119 ꢀC (from
ethanol; lit.48 116–118 ꢀC); 1H NMR (300 MHz; CDCl3) d 5.81 (s, 1H),
7.16 (t, J¼7.4 Hz,1H), 7.29–7.38 (m, 2H), 7.47–7.58 (m, 4H), 7.60–7.69
(m, 1H), 8.03–8.12 (m, 2H), 8.41 (s, 1H, NH).
0.7 Hz, 1H), 7.71–7.76 (m, 1H); 19F NMR (285 MHz; CDCl3) d ꢁ82.4;
IR nmax(KBr)/cmꢁ1 3378 (OH), 1649, 1464, 1402, 1175, 1120, 1090,
1005, 977, 770, 716; MS m/z (EI, 70 eV) 350 (2%, Mþ), 236 (25%), 95
(100%), 69 (25%); high resolution MS m/z 349.9270 (calcd for
C8H6F3IO4: 349.9263). Anal. Calcd for C8H6F3IO4 C, 27.45; H, 1.73.
Found: C, 27.29; H, 1.71.
4.3.5. 2-Bromo-3-oxo-3,N-diphenylpropionamide49 (7b)
Crude product was crystallized (85%), mp 133–134 ꢀC (from
ethanol; lit.49 132–123.5 ꢀC).
4.3.12. 2-Iodo-4,4,4-trifluoro-3,3-dihydroxy-1-thiophen-2-ylbutan-
1-one (13c)
Crude product was crystallized (79%), mp 100–101 ꢀC (from
CHCl3, decomposition); 1H NMR (300 MHz; CDCl3) d 4.36 (s, 1H,
OH), 5.55 (s, 1H, CHI), 5.83 (s, 1H, OH), 7.19–7.28 (m, 1H, ArH), 7.80–
7.91 (m, 2H, ArH); 19F NMR (285 MHz; CDCl3) d ꢁ82.2; IR nmax(KBr)/
cmꢁ1 3337 (OH), 3217 (OH), 1632, 1409, 1204, 1172, 1067, 735; MS
m/z (EI, 70 eV) 366 (4%, Mþ), 153 (18%), 111 (100%), 69 (28%); high
resolution MS m/z 365.9049 (calcd for C8H6F3IO3S: 365.9034). Anal.
Calcd for C8H6F3IO3S C, 26.25; H, 1.65. Found: C, 26.24; H, 1.70.
4.3.6. 2-Iodo-3-oxo-3,N-diphenylpropionamide50 (7c)
Crude product was crystallized (83%), mp 131–134 ꢀC (from
ethanol; lit.50 138–140 ꢀC); 1H NMR (300 MHz; CDCl3) d 5.92 (s, 1H,
CHI), 7.14 (t, J¼7.4 Hz, 1H), 7.34 (t, J¼7.9 Hz, 2H), 7.51 (t, J¼7.6 Hz,
2H), 7.56–7.71 (m, 3H), 8.02 (d, J¼7.3 Hz, 2H), 9.63 (s, 1H, NH).
4.3.7. 2-Chloro-4,4,4-trifluoro-3,3-dihydroxy-1-phenylbutan-1-
one (11a)
Crude product was crystallized (71%), mp 74–75 ꢀC (from
CHCl3); 1H NMR (300 MHz; CDCl3) d 4.43 (s,1H), 5.36 (s,1H), 5.56 (s,
1H), 7.54–7.60 (m, 2H), 7.69–7.75 (m, 1H), 7.99–8.04 (m, 2H); 19F
NMR (285 MHz; CDCl3) d ꢁ83.0; IR nmax(KBr)/cmꢁ1 3387 (OH), 1671,
1595, 1208, 1175, 1090, 1007, 970, 683, 630; MS m/z (EI, 70 eV), 269
(10%, MHþ), 154 (30%),105 (100%), 77 (62%); high resolution MS m/z
269.0202 (MHþ; calcd for C10H8ClF3O3: 269.0192). Anal. Calcd for
4.4. Dibromination of ketones (22a–d) under SFRC: general
procedure
Ketone (1 mmol) and N-bromosuccinimide (NBS, 2 mmol) were
triturated together with PTSA (0.1 mmol) in a porcelain mortar for
2 min. The reaction mixture was then heated to 80 ꢀC for 1 h,
turning it into a dense paste. Water was then added (5 mL) followed
by extraction with tert-butyl methyl ether or CH2Cl2 (20 mL). The
organic phase was washed with water (10 mL), dried over Na2SO4
and solvent evaporated under reduced pressure.
C
10H8ClF3O3 C, 44.71; H, 3.00. Found: C, 44.49; H, 3.01.
4.3.8. 2-Chloro-4,4,4-trifluoro-1-furan-2-yl-3,3-dihydroxybutan-1-
one (11b)
Crude product was crystallized (74%), mp 79–80 ꢀC (from
CHCl3); 1H NMR (300 MHz; CDCl3) d 4.37 (s, 1H, OH), 5.26 (s, 1H,
CHCl), 5.37 (s, 1H, OH), 6.70 (dd, J¼3.7, 1.7 Hz, 1H, ArH), 7.51 (dd,
J¼3.7, 0.7 Hz, 1H, ArH), 7.78 (dd, J¼1.7, 0.7 Hz, 1H, ArH); 19F NMR
(285 MHz; CDCl3) d ꢁ83.1; IR nmax(KBr)/cmꢁ1 3355 (OH), 1660,
1570, 1464, 1328, 1206, 1174, 1136, 1087, 986, 722, 658; MS m/z (EI,
70 eV) 258 (9%, Mþ), 144 (20%), 95 (100%), 68 (15%); high resolution
MS m/z 257.9914 (calcd for C8H6ClF3O4: 257.9907). Anal. Calcd for
C8H6ClF3O4 C, 37.16; H, 2.34. Found: C, 37.51; H, 2.39.
4.4.1. 2,2-Dibromoindanone51 (24a)
Crude product (99%) was crystallized, mp 132–133 ꢀC (from
ethanol; lit.51 133–134 ꢀC).
4.4.2. 2,2-Dibromo-5-methoxyindan-1-one1 (24b)
Crude product (98%) was crystallized, mp 109–110 ꢀC (from
ethanol; lit.1 109–110 ꢀC).
4.4.3. 2,2-Dibromo-1-tetralone32 (24c)
4.3.9. 2-Chloro-4,4,4-trifluoro-3,3-dihydroxy-1-thiophen-2-
ylbutan-1-one (11c)
Crude product (88%) was crystallized, mp 57–58 ꢀC (from eth-
anol; lit.32 58–60 ꢀC); 13C NMR (76 MHz; CDCl3) d 29.3 (CH2), 45.8
(CH2), 67.1 (CBr2), 127.3 (ArC), 127.5 (ArCH), 128.6 (ArCH), 130.0
(ArCH), 134.4 (ArCH), 142.0 (ArC), 184.1 (CO).
Crude product was crystallized (80%), mp 97–98 ꢀC (from
CHCl3); 1H NMR (300 MHz; CDCl3) d 4.47 (s, 1H), 5.19 (s, 1H), 5.49 (s,
1H), 7.21–7.29 (m, 1H), 7.87–7.93 (m, 2H); 19F NMR (285 MHz;
CDCl3) d ꢁ82.9; IR nmax(KBr)/cmꢁ1 3354 (OH),1645,1410,1198,1133,
1092, 864, 733; MS m/z (EI, 70 eV) 274 (2%, Mþ), 111 (100%), 84
(15%), 69 (12%); high resolution MS m/z 273.9688 (calcd for
C8H6ClF3O3S: 273.9678); Anal. Calcd for C8H6ClF3O3S C, 34.99; H,
2.20. Found: C, 35.20; H, 2.27.
4.4.4. 2,2-Dibromo-6-methoxy-1-tetralone52 (24d)
Crude product (70%) was crystallized, mp 78–80 ꢀC (from eth-
anol; lit.52 85 ꢀC).
4.3.10. 2-Iodo-4,4,4-trifluoro-3,3-dihydroxy-1-phenylbutan-1-
one (13a)
4.5. The effect of preorganization of substrates (PO) and
addition of solvent (AD) on the bromination of 22a, 22c
and 28 with NBS
Crude product was crystallized (86%), mp 90–92 ꢀC (from CHCl3,
decomposition); 1H NMR (300 MHz; CDCl3) d 4.37 (s, 1H), 5.70 (s,
1H), 5.92 (s, 1H), 7.50–7.59 (m, 2H), 7.66–7.74 (m, 1H), 7.96–8.01 (m,
2H); 19F NMR (285 MHz; CDCl3) d ꢁ82.2; IR nmax(KBr)/cmꢁ1 3383
(OH), 1659, 1204, 1175, 1066, 968, 728, 683, 623; MS m/z (EI, 70 eV)
360 (2%, Mþ), 147 (20%), 105 (100%), 77 (50%), 69 (27%); high res-
olution MS m/z 359.9483 (calcd for C10H8F3IO3: 359.9470). Anal.
Calcd for C10H8F3IO3 C, 33.36; H, 2.24. Found: C, 33.17; H, 2.26.
PO: NBS (0.5 mmol) and PTSA (0.05 mmol) were first dissolved
in MeOH or MeCN (2.5 mL), and substrate (0.5 mmol) was then
added. Evaporation of solvent under reduced pressure (bath tem-
perature 20 ꢀC) was then performed for 5 min. Reaction was
quenched with NaHSO3 either after the described evaporation of
solvent, or 25 min later (see Table 4).
AD: Substrate (0.5 mmol), NBS (0.5 mmol), PTSA (0.05 mmol)
and 5 drops of cold MeOH (1.5 mmol) were mixed in a porcelain
mortar. A pasty mixture resulted and the mortar was then covered
to prevent solvent evaporation. Reaction was quenched with
NaHSO3 after 5 min at room temperature and the usual isolation
procedure was performed.
4.3.11. 2-Iodo-4,4,4-trifluoro-1-furan-2-yl-3,3-dihydroxybutan-1-
one (13b)
Crude product was crystallized (87%), mp 91–93 ꢀC (from CHCl3,
decomposition); 1H NMR (300 MHz; CDCl3) d 4.36 (s, 1H, OH), 5.62
(s, 1H), 5.73 (s, 1H, OH), 6.68 (dd, J¼3.7, 1.7 Hz, 1H), 7.48 (dd, J¼3.7,

I. Pravst et al. / Tetrahedron 64 (2008) 5191–5199
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4.6. Determination of rate order constants for functionali-
zation of 1-phenylethanone (1), 1-(4-methoxy-
phenyl) (25a) and 1-(4-trifluoromethyl)-ethanone
(25e) with NBS under SFRC at 40 8C
To a thermostatted mixture of substrate (2 mmol) and PTSA,
NBS (2 mmol) was added. The flask with reaction mixture was then
rotated in a thermostatted bath using a Bu¨chi R124 apparatus.
During reaction, some of the reaction mixture was removed from
the flask into a water solution of NaHSO3 (quenching) and after
micro-isolation with CDCl3, conversion was determined using 1H
NMR. First order rate constants were calculated from Eq. 1:
40 ꢀC
ln[(n0ꢁnt)/n0]¼kBrt and a linear relationship was found with k
Br
1.6ꢂ10ꢁ3, 1.8ꢂ10ꢁ3 and 0.6ꢂ10ꢁ3 sꢁ1 for 1, 25a and 25b, re-
spectively, with R2 being over 0.99. These results were determined
to be reproducible while first rate order was also confirmed by
experiments using a different substrate–NBS ratio.
Relative reactivities of ketones 1, 22a–c, 25a–c,e,f, 30a–c were
determined by competitive reactions with NBS under SFRC at 20 ꢀC
as follows: Substrate (1 mmol) and acetophenone (1, 1 mmol) were
triturated together with PTSA (0.1 mmol) in porcelain mortar for
2 min. NBS(1 mmol) was added totheliquidreactionmixture, which
was then triturated for 2 min. After 24 h, water was added (10 mL),
followed by usual extraction procedure. Product mixture was ana-
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lyzed using 1H NMR. Applying this known competitive technique,
rel
relative rate factors (kBrerl) were calculated from Eq. 2: k ¼kA/
Br
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amounts of compounds in the reaction mixture after reaction time).
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This research was supported by the Slovenian Research Agency
(ARRS, programme P1-0134) and the Young Researcher Programme
(24300dI.P.) of the Republic of Slovenia. We are grateful to the staff
of the National NMR Centre at the National Institute of Chemistry in
Ljubljana, the staff of the Mass Spectroscopy Centre at the ‘Jozef
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ˇ
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