Facile aerobic photo-oxidative synthesis of phenacyl iodides and bromides from styrenes using I2 or aqueous HBr

Article abstract of DOI:10.1055/s-0030-1258022

We report a useful method for facile synthesis of phenacyl iodides and bromides from styrene derivatives by aerobic photo-oxidation using I₂ or 48% aqueous HBr in the presence of water. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258022

LETTER
2335
Facile Aerobic Photo-Oxidative Synthesis of Phenacyl Iodides and Bromides
from Styrenes Using I2 or Aqueous HBr
A
erobic Photo-O
o
xidation moya Nobuta, Shin-ichi Hirashima, Norihiro Tada, Tsuyoshi Miura, Akichika Itoh*
Gifu Pharmaceutical University 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan
Fax +81(58)2308108; E-mail: itoha@gifu-pu.ac.jp
Received 15 June 2010
16). In the course of our further studies of this reaction, we
Abstract: We report a useful method for facile synthesis of phena-
cyl iodides and bromides from styrene derivatives by aerobic photo-
oxidation using I2 or 48% aqueous HBr in the presence of water.
found that aerobic photo-oxidative syntheses of phenacyl
iodides from styrenes took place in the presence of a small
amount of water instead of FSM-16. In addition, we also
succeeded in synthesizing phenacyl bromides by aerobic
photo-oxidation of styrenes with 48% aqueous HBr
(Scheme 1). Herein, we report a detailed study of direct
aerobic photo-oxidative syntheses of phenacyl halides
from styrenes.
Key words: aerobic, photo-oxidation, phenacyl iodide, phenacyl
bromide, styrene
Phenacyl halides play an important role as key intermedi-
ates in organic syntheses, since they have been used as
precursors of various pharmaceutically important het-
eroaromatics such as imidazoles, selenazoles, and ox-
azoles.1 Especially it is well known that phenacyl halides
are coupled with thioamides to provide the corresponding
thiazoles, so-called Hantzsch synthesis.2 As another ex-
ample, phenacyl iodides react with 2-methoxy furans or 5-
O
O2, hν (VIS)
aq HBr, H2O
O2, hν (VIS)
I2, H2O
O
I
Br
Ar
Ar
Ar
Scheme 1
methoxy oxazoles in the presence of catalytic NaI to pro- Table 1 shows the results of reaction conditions for aero-
vide butenolides or azalactones, respectively.3 Phenacyl bic photo-oxidative synthesis of phenacyl iodide 2 from 4-
bromides are condensed with aldehydes through Wittig- tert-butyl styrene (1) as a test substrate. Among our data,
type reaction in the presence of a catalytic amount of tel- it was found that molecular iodine was the best iodine
luride reagents to give a,b-unsaturated esters.4
source and addition of H2O (50 mL) significantly im-
proves the yield of 2 up to 82% (entries 1–5). Among the
solvents examined, ethyl acetate was the most suitable
solvent (entries 5 and 9–14). As a result of further exami-
nations, the optimal result was obtained in the presence of
I2 (0.6 equiv) and H2O (80 mL) in ethyl acetate (3 mL, en-
try 6). Interestingly, only 0.6 equivalents of I2 were re-
quired for the synthesis of phenacyl iodide 2. Both visible-
light irradiation and molecular oxygen are necessary for
the oxidation since 2 could not be obtained at all without
them (entries 7 and 8).
The syntheses of such useful phenacyl halides have been
studied by many groups, and there are two types of meth-
ods, that use acetophenones or styrenes as a starting mate-
rial.5–16 Acetophenones are easily transformed to the
phenacyl halides. However, styrenes are more suitable for
large-scale synthesis than acetophenones since they are
less expensive. Furthermore, this reaction includes two
steps, oxidation and halogenation, and is thought to have
much attention from the viewpoint of reduction of energy
consumption, labor and solvents, and the development of
tandem reactions has been a fertile field in organic synthe- Table 2 shows the results of reaction conditions for aero-
sis; however, only few methods, which require heavy- bic photo-oxidative synthesis of phenacyl bromides 3
metal reagent,17 low atom-efficient organic compound,18 from 1. Among the bromine sources we examined, 48%
and excess halogen sources,19 have been reported.
aqueous HBr was found to be most effective, and molec-
ular bromine, which added to the double bond preferen-
tially, was not suitable for synthesis of 3 (entries 1–4).
Similarly to the synthesis of phenacyl iodides, addition of
H2O was found to be effective, and ethyl acetate was
found to be the most suitable solvent (entries 5, 9–14).
Among our examinations, the optimal result was obtained
in the presence of 48% aqueous HBr (1.1 equiv) and H2O
(50 mL) for 7 hours (entry 6). The fact that 3 was obtained
only in low yield or not obtained at all without either vis-
ible-light irradiation or molecular oxygen shows the ne-
cessity of both for this reaction (entries 7 and 8).
With this perspectives, we have previously reported aero-
bic photo-oxidative synthesis of phenacyl iodides from
styrenes with molecular iodines and FSM-16, a mesopo-
rous silica.20 This method is valuable towards green
chemistry due to use of visible light from general-purpose
fluorescent lamp, molecular oxygen as a terminal oxidant
that generate theoretically only water as end product, and
environmental low impact solvent; however, this method
require a considerable quantity of solid catalyst (FSM-
SYNLETT 2010, No. 15, pp 2335–2339
x
x
.x
x
.2
0
1
0
Table 3 presents the scope and limitation of the aerobic
photo-oxidative syntheses of phenacyl halides from sty-
Advanced online publication: 09.08.2010
DOI: 10.1055/s-0030-1258022; Art ID: U05510ST
© Georg Thieme Verlag Stuttgart · New York

2336
T. Nobuta et al.
LETTER
Table 1 Study of Reaction Conditions for Photo-Oxidative Synthe-
sis of 4-tert-Butylphenacyl Iodide (2)
Table 2 Study of Reaction Conditions for Photo-Oxidative Synthe-
sis of 4-tert-Butylphenacyl Bromide (3)
O
O
O2, hν (VIS)
iodine source, additive
O2, hν (VIS)
bromine source, additive
Br
I
t-Bu
solvent, 10 h
t-Bu
solvent (5 mL)
t-Bu
t-Bu
1 (0.3 mmol)
2
3
1 (0.3 mmol)
Entry Iodine source
(equiv)
Additive
(mL)
Solvent
(mL)
Yield
(%)a
Entry Bromine source
(equiv)
Additive
(mL)
Solvent
Time Yield
(h) (%)a
1
2
CaI2 (1.0)
NIS (1.0)
55% aq HI (1.0)
I2 (1.0)
–
EtOAc (5)
EtOAc (5)
EtOAc (5)
EtOAc (5)
EtOAc (5)
EtOAc (3)
EtOAc (3)
EtOAc (3)
THF (5)
23
33
61
66
82
84 (85)
0b
1
2
3
4
5
6
7
8
9
Br2 (1.2)
–
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
acetone
MeOH
MeCN
i-Pr2O
hexane
H2O
10
10
1
2
–
NBS (1.2)
–
3
–
MgBr2·OEt2 (1.2)
48% aq HBr (1.2)
48% aq HBr (1.2)
48% aq HBr (1.1)
48% aq HBr (1.1)
48% aq HBr (1.1)
48% aq HBr (1.2)
–
10 36
10 54
10 67
4
–
–
5
I2 (1.0)
H2O (50)
H2O (80)
H2O (80)
H2O (80)
H2O (50)
H2O (50)
H2O (50)
H2O (50)
H2O (50)
H2O (50)
H2O (50)
H2O (50)
H2O (50)
H2O (50)
H2O (50)
H2O (50)
H2O (50)
H2O (50)
H2O (50)
H2O (50)
6
I2 (0.6)
7
7
7
73 (74)
16b
0c
7
I2 (0.6)
8
I2 (0.6)
0c
9
I2 (1.0)
78
75
65
64
15
0
10 11
10
11
12
13
14
I2 (1.0)
i-Pr2O (5)
hexane (5)
MeCN (5)
acetone (5)
MeOH (5)
10 48% aq HBr (1.2)
11 48% aq HBr (1.2)
12 48% aq HBr (1.2)
13 48% aq HBr (1.2)
14 48% aq HBr (1.2)
10
10
10
10
10
8
6
0
0
0
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
a 1H NMR yields. Number in parenthesis is isolated yield.
b The reaction was carried out in the dark.
a 1H NMR yields. Number in parenthesis is isolated yield.
b The reaction was carried out in the dark.
c The reaction was carried out under N2 atmosphere.
c The reaction was carried out under N2 atmosphere.
renes under the optimized conditions mentioned above.21
Generally, the corresponding phenacyl halides were ob-
tained in good yields regardless of an electron-donating or
electron-withdrawing group at aromatic ring (entries 1–5,
11–14). It was worth noting that electron-poor substrates,
which could not be successfully used in the previous re-
ports,18b,c were smoothly oxidized to afford the corre-
sponding phenacyl halides in good to high yields (entries
11–14). Since methyl group at aromatic ring was oxidized
by molecular oxygen in the presence of bromine source,
yields of 9 and 12 were moderate and low, respectively
(entries 6 and 8).22 Since steric hindrance retarded the re-
action, 11 and 2-iodo-1-(2-methylphenyl) ethanol were
obtained in 43% and 27% yields, respectively (entry 7).
NIS was used as iodine source when using 4-methoxysty-
rene (13) as substrate since polymerization was occurred
when using molecular iodine (entry 9). Unfortunately, 13
was a poor substrate for the synthesis of the corresponding
phenacyl bromide 15 (entry 10). 2-Vinylnaphthalene (22)
was oxidized to provide the corresponding phenacyl ha-
lides (23 and 24) in moderate yields (entry 15 and 16).
Furthermore, 2-vinylpyridine (25), which is a heterocy-
clic compound, could be transformed to the corresponding
phenacyl iodide 26 or phenacyl bromide 27 in good or
moderate yields, respectively, with NIS or NBS (entries
17 and 18). Although b-substituted styrenes (28 and 31)
and aliphatic alkene (34) also reacted with HBr to afford
the corresponding phenacyl bromides (30 and 33) or a-
bromo ketone (35) in moderate or low yields, the corre-
sponding phenacyl iodide and a-iodo ketones were not
obtained (entry 19–24).
We also attempted to scale up the synthesis of phenacyl
iodides under the optimized condition mentioned above;
however, 2 was obtained from 1 only in low yield due to
formation
of
1-ethoxy-2-iodo-1(4-tert-buthylphe-
nyl)ethane by addition of iodine and ethanol which arose
from hydrolysis of ethyl acetate. Therefore, THF, which
showed similar activity compared with ethyl acetate, was
used as a solvent (Table 1, entry 9), and 2 was obtained in
good yield even at 10 mmol scale (Scheme 2).
O
O2, hν (VIS)
I2 (0.6 equiv), H2O (2.7 mL)
I
t-Bu
1 (10 mmol)
THF (100 mL), 52 h
t-Bu
2 75%
Scheme 2 Large-scale synthesis of phenacyl iodide
Synlett 2010, No. 15, 2335–2339 © Thieme Stuttgart · New York

LETTER
Aerobic Photo-Oxidation
2337
Table 3 Aerobic Photo-Oxidative Syntheses of Phenacyl Halides from Styrenes
O2, hν (VIS)
method A or B
O
Ar
X
Ar
(0.3 mmol)
Entry
Substrate
Methoda
Time (h)
Product
Yield (%)b
O
X
1
2
A
B
10
7
2 X =1
3 X = Br
85
74
X
t-Bu
1
t-Bu
O
3
4
A
B
10
7
5 X = I
6 X = Br
77
74
4
O
5
6
A
B
10
5
8 X = I
9 X = Br
88
50
X
7
O
7
8
A
B
10
5
11 X = I
12 X = Br
43
22
X
10
O
9
10
A
B
7
7
14 X = I
76c
X
15 X = Br
trace
MeO
MeO
13
O
11
12
A
B
10
7
17 X = I
18 X = Br
78
84
X
Cl
Cl
16
O
O
13
14
A
B
15
12
20 X = I
21 X = Br
67
86
X
X
O2N
O2N
19
15
16
A
B
24
7
23 X = I
24 X = Br
46
48
22
O
O
O
N
17
18
A
B
7
10
26 X = I
27 X = Br
72c
39d
N
X
X
X
25
28
31
19
20
A
B
10
7
29 X = I
30 X = Br
trace
45
Ph
21
22
A
B
10
7
32 X = I
33 X = Br
0
41
Ph
X
O
23
24
A
B
10
10
35 X = I
36 X = Br
tracee
28f
11
11
34
a Method A: with I2 (0.6 equiv), H2O (80 mL), EtOAc (3 mL). Method B: with 48% aq HBr (1.1 equiv), H2O (50 mL), EtOAc (5 mL).
b Isolated yields.
c With NIS (1.2 equiv), H2O (180 mL), EtOAc (5 mL).
d With NBS (1.2 equiv), H2O (50 mL).
e With I2 (1.0 equiv), EtOAc (5 mL).
f With 48% aq HBr (1.5 equiv).
Synlett 2010, No. 15, 2335–2339 © Thieme Stuttgart · New York

2338
T. Nobuta et al.
LETTER
OH
O
O
O2, hν (VIS)
48% aq HBr (1.1 equiv)
H2O (50 μL)
Br
Br
Br
+
(1)
(2)
Br
EtOAc (5 mL), 5 h
37 (0.3 mmol)
6 54%
38 26%
N2, hν (VIS)
I2 (0.6 equiv)
H2O (80 μL)
OH
I
EtOAc (3 mL), 10 h
t-Bu
t-Bu
1 (0.3 mmol)
39 0%
OH
N2, hν (VIS)
48% aq HBr (1.1 equiv)
H2O (50 μL)
Br
(3)
EtOAc (5 mL), 7 h
t-Bu
t-Bu
40 trace
1 (0.3 mmol)
Scheme 3 Studies of reaction mechanism
To clarify the reaction mechanism, 2-bromo-1-phenyl- from molecular iodine or bromine. The radical species 41
ethanol (37), which is presumed as an intermediate, was traps molecular oxygen to afford hydroperoxides 43 via
subjected to similar aerobic photo-oxidative conditions, peroxy radical species 42. Halohydrines 44, which are
and 6 was obtained in 54% yield (Scheme 3, equation 1). given by reduction of 43 by hydrogen halides, are trans-
This indicates that the reaction proceeds through the halo- formed to the benzyl radical species 45 with halogen rad-
hydrins as an intermediate. In addition, the results that we ical or peroxy radical species 42. Finally, phenacyl halides
could not obtain 39 and 40 when 1 was subjected to the are provided via geminal diols 46 by the similar oxida-
conditions without oxygen suggested that carbonyl oxy- tions of 45 as mentioned above. The role of water has not
gen of phenacyl halides is originated from molecular ox- been clarified yet; however, we presume that it may sup-
ygen, not from water (Scheme 3, equations 2 and 3). press overoxidation because a trace amount of 4-tert-
Furthermore, the yellow color of the reaction mixture in- butylbenzaldehyde, which is not generated under the reac-
dicates formation of bromine during the reaction.
tion conditions in the presence of water, is detected by 1H
NMR when 1 is subjected to the reaction conditions of
synthesis of phenacyl iodides without water (Table 1, en-
try 4).
Scheme 4 shows a plausible path of this oxidation, which
is postulated by considering all of the results mentioned
above and the necessity of molecular oxygen and contin-
uous light irradiation in this reaction. We believe that the In conclusion, we have developed an efficient synthesis of
benzyl radical species 41 is generated by addition of halo- phenacyl halides in the presence of water and halogen
gen radicals, which are formed by irradiation of VIS light sources such as molecular iodine or 48% aqueous HBr un-
hν
1) I2
I
O2, hν
hν
HBr
Br2
Br
O
O
solvent or
HX or 44
X
O2
X
X
X
2)
Ar
Ar
Ar
Ar
Ar
Ar
(X = I, Br)
41
42
OH
X
X
HX
HX
X2
OH
O
OH
O2
X
Ar
Ar
44 (1H NMR)
43
45
HX
X2
OH
OH
OH
O
solvent or
O
X
X
X
HX or 44
Ar
X
O
OH
Ar
OH
O
46
Scheme 4 Plausible path for aerobic photo-oxidation of styrenes to phenacyl halides
Synlett 2010, No. 15, 2335–2339 © Thieme Stuttgart · New York

LETTER
Aerobic Photo-Oxidation
2339
(21) Typical Procedure for the Synthesis of 4-tert-
der visible-light irradiation with fluorescent lamps. This
method is of great value from the viewpoint of green
chemistry and organic synthesis because of using inex-
pensive styrenes, halogen sources such as molecular io-
dine or 48% aqueous HBr, harmless visible light
irradiated from a general purpose fluorescent lamp, and
molecular oxygen as terminal oxidant. Further application
of this photo-oxidation to other reactions is now in
progress in our laboratory.
Butylphenacyl Iodide (2, Table 3, Entry 1)
A solution of 4-tert-butylstyrene (1, 0.3 mmol), I2 (0.18
mmol), and H2O (80 mL) in dry EtOAc (3 mL) in a Pyrex test
tube, purged with an O2 balloon, was stirred and irradiated
externally with four 22 W fluorescent lamps for 10 h. The
reaction mixture was washed with aq Na2S2O3 and brine, and
concentrated in vacuo. Purification of the crude product by
PTLC (hexane–EtOAc = 5:1)provided 4-tert-butylphenacyl
iodide (Rf = 0.50, 77.0 mg, 85%).
4-tert-Butylphenacyl Iodide (2)
1H NMR (500 MHz, CDCl3): d = 7.93 (d, J = 8.8 Hz, 2 H),
7.49 (d, J = 8.8 Hz, 2 H), 4.34 (s, 2 H), 1.35 (s, 9 H). 13
C
References and Notes
NMR (125 MHz, CDCl3): d = 192.6, 157.8, 131.0, 129.1,
125.9, 35.3, 31.2, 1.9. HRMS (EI+): m/z calcd for C12H15OI
[M+]: 302.0168; found: 302.0174.
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Yorimitsu, H.; Oshima, K. Synthesis 2005, 824.
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2-Methylphenacyl Iodide (11)
1H NMR (500 MHz, CDCl3): d = 7.67 (d, J = 7.4 Hz, 1 H),
7.41 (t, J = 7.4 Hz, 1 H), 7.29–7.25 (m, 2 H), 4.33 (s, 2 H),
2.51 (s, 3 H). 13C NMR (125 MHz, CDCl3): d = 195.8, 139.9,
134.4, 132.3, 128.9, 125.8, 21.5, 5.8. MS (EI+): m/z (%) =
260 [M+], 133, 119 (100), 105, 91, 65.
2-Iodo-1-(2-naphthalenyl)ethanone (23)
1H NMR (500 MHz, CDCl3): d = 8.51 (s, 1 H), 8.03–7.96
(m, 2 H), 7.91–7.87 (m, 2 H), 7.63–7.55 (m, 2 H), 4.48 (s, 2
H). 13C NMR (125 MHz, CDCl3): d = 193.0, 135.9, 132.5,
131.1, 130.9, 129.8, 129.1, 128.9, 128.0, 127.1, 124.5, 1.9.
HRMS (EI+): m/z calcd for C12H9OI [M+]: 295.9699; found:
295.9693.
2-Iodo-1-(2-pyridinyl)ethanone (26)
1H NMR (500 MHz, CDCl3): d = 8.70 (d, J = 4.0 Hz, 1 H),
8.10 (d, J = 6.8 Hz, 1 H), 7.89–7.86 (m, 1 H), 7.53–7.50 (m,
1 H), 4.69 (s, 2 H). 13C NMR (125 MHz, CDCl3): d = 194.5,
150.8, 149.2, 137.2, 127.8, 123.0, 1.9. HRMS (EI+): m/z
calcd for C7H6NOI [M+]: 246.9494; found: 246.9503.
4-tert-Butylphenacyl Bromide (3)
1H NMR (500 MHz, CDCl3): d = 7.92 (d, J = 8.8 Hz, 2 H),
7.50 (d, J = 8.8 Hz, 2 H), 4.43 (s, 2 H), 1.35 (s, 9 H). 13
C
NMR (125 MHz, CDCl3): d = 191.0, 158.0, 131.4, 129.0,
126.0, 35.3, 31.3, 31.1. HRMS (EI+): m/z calcd for
C12H15OBr [M+]: 254.0306; found: 254.0314.
2007, 3113.
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2-Bromo-1-(2-pyridinyl)ethanone (27)
1H NMR (500 MHz, CDCl3): d = 8.70 (d, J = 4.6 Hz, 1 H),
8.11 (d, J = 8.0 Hz, 1 H), 7.90–7.87 (m, 1 H), 7.54–7.52 (m,
1 H), 4.87 (s, 2 H). 13C NMR (125 MHz, CDCl3): d = 192.6,
151.5, 149.3, 137.3, 127.9, 122.8, 32.6. HRMS (EI+): m/z
calcd for C7H6NOBr [M+]: 198.9633; found: 198.9641.
2-Bromo-1-phenyl-1-propanone (30)
1H NMR (500 MHz, CDCl3): d = 8.04–8.02 (m, 2 H), 7.61–
7.58 (m, 1 H), 7.51–7.48 (m, 2 H), 5.30 (q, J = 6.9 Hz, 1 H),
1.91 (d, J = 6.9 Hz, 3 H). 13C NMR (125 MHz, CDCl3):
d = 193.4, 134.1, 133.8, 129.0, 128.9, 41.5, 20.2. MS (EI+):
m/z (%) = 212 [M+], 105 (100), 77, 51.
1-Bromo-2-dodecanone (36)
1H NMR (500 MHz, CDCl3): d = 3.89 (s, 2 H), 2.65 (t,
J = 7.5 Hz, 2 H), 1.63–1.58 (m, 2 H), 1.29–1.26 (m, 14 H),
0.88 (t, J = 6.9 Hz, 3 H). 13C NMR (125 MHz, CDCl3):
d = 202.4, 40.0, 34.4, 32.0, 29.6, 29.5, 29.4, 29.4, 29.1, 24.0,
22.8, 14.2. LRMS (FAB+): m/z (%) = 263 [M+ + 1], 120, 107,
89, 77, 65, 55, 41.
(20) Nakayama, H.; Itoh, A. Tetrahedron Lett. 2007, 48, 1131.
(22) (a) Sugai, T.; Itoh, A. Tetrahedron Lett. 2007, 48, 9096.
(b) Hirashima, S.; Itoh, A. Photochem. Photobiol. Sci. 2007,
6, 521.
Synlett 2010, No. 15, 2335–2339 © Thieme Stuttgart · New York

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