Nonselective bromination-selective debromination strategy: Selective bromination of unsymmetrical ketones on singly activated carbon against doubly activated carbon

Article abstract of DOI:10.1021/ol0271638

(Matrix presented) We have found a new synthetic method for the preparation of the α-bromoketones that are brominated in the less activated terminal position of unsymmetrical ketones. Brominations in short reaction times (kinetically controlled) provided internally brominated compounds as a major product. However, brominations in longer reaction times (thermodynamically controlled) gave more of the terminally brominated compound through the reversible reaction by Br₂ and produced hydrogen bromide. Several brominated compounds at the terminal position were successfully prepared through the new synthetic route.

Full text of DOI:10.1021/ol0271638

ORGANIC
LETTERS
2
003
Vol. 5, No. 4
11-414
Nonselective Bromination−Selective
Debromination Strategy: Selective
Bromination of Unsymmetrical Ketones
on Singly Activated Carbon against
Doubly Activated Carbon
4
Han Young Choi and Dae Yoon Chi*
Department of Chemistry, Inha UniVersity, 253 Yonghyundong Namgu,
Inchon 402-751, Korea
dychi@inha.ac.kr
Received October 24, 2002
ABSTRACT
We have found a new synthetic method for the preparation of the r-bromoketones that are brominated in the less activated terminal position
of unsymmetrical ketones. Brominations in short reaction times (kinetically controlled) provided internally brominated compounds as a major
product. However, brominations in longer reaction times (thermodynamically controlled) gave more of the terminally brominated compound
through the reversible reaction by Br and produced hydrogen bromide. Several brominated compounds at the terminal position were successfully
2
prepared through the new synthetic route.
Recently, we reported regio- and substituent-selective de-
bromination reaction on activated aromatic bromine by
hydrobromic acid and a scavenger. Therein, the ipso-
Through this investigation, we could obtain debrominated
products of R-bromocarbonyls in around 90% yield (Table
1). Although there were many reports on isomerization of
1
protonated compound 1 is the intermediate of the debromi-
nation reaction as shown in Figure 1. The protonated
Table 1. Reductive Debromohydrogenation Reactions of
R-Bromocompounds in Concentrated HBr/AcOH Conditions
a
scavengerb (equiv)
yield (%)c
entry
reactant
time (h)
1
2
3b
4b
4
3
1.15
1.15
3a (89)
4a (92)
Figure 1. Mechanism of reductive debromination of bromophenol
and the structure similarity between intermediate 1 and protonated
R-bromoketone.
a
At reflux. b Na2S2O4. c Isolated yield.
R-bromoketone 2 has the same scaffold as intermediate 1
shown boxed in Figure 1. We have checked whether or not
R-bromoketones could also be reduced by the same reducing
2
R-bromoketones by HBr, this is the first report where HBr
is used as a reducing agent of R-bromoketone. During this
system (HBr/scavenger of Br
2
).
(1) Choi, H. Y.; Chi, D. Y. J. Am. Chem. Soc. 2001, 123, 9202-9203.
1
0.1021/ol0271638 CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/21/2003

1
4
study of bromination and debromination processes of ali-
phatic ketones, we also have discovered the selective
bromination of unsymmetrical ketones on singly activated
carbon against doubly activated carbon, which will provide
a new general synthetic route for the preparation of bromi-
nated unsymmetrical ketones in a less activated position
telluroates, thiols,15 selenols,16 amines,17 and anionic iron
1
8
19
complex; (iii) heterogeneous hydrogenation; and (iv)
20
homogeneous Pd-catalyzed hydrogenation. However, to our
knowledge, there has been no report on hydrobromic acid
as a reducing agent of R-bromoketones.
During our research on the possibility of hydrobromic acid
as a reducing agent, we found that the addition of hydro-
bromic acid causes reversible isomerization such as those
(Scheme 1). Unsymmetrical ketones such as phenylacetone
2
published reports and discovered that HBr causes irreversible
debromination when added with a scavenger of bromine (first
Scheme 1. New Synthetic Strategy for the Selective
Preparation of Terminal Bromoketones
discoVery). We also found that the doubly activated internal
21
position is more rapidly brominated and debrominated than
the singly activated terminal position (second discoVery).
In the case of bromination at the more activated R-position
of unsymmetrical ketones, the required R-bromoketones can
be obtained by direct bromination. However, there is a
synthetic difficulty in the preparation of R-bromoketones
brominated at the less activated R-position. There are some
reports on synthetic methods of unsymmetrically brominated
(
5) and 1-phenyl-1,3-butanedione (6) have a methylene group
and a methyl group. In this report, the methylene carbon is
in an internal position that is doubly activated by two
electron-withdrawing groups (EWG): phenyl and carbonyl
or two carbonyls. In addition, the methyl carbon is in a
terminal position singly activated by only one carbonyl.
2
2
R-ketones: bromination of epoxides, oxidation of olefins
2
3
24
by sodium bromite, bromodecarboxylations, and bromo-
2
5
deacylations; however, all of them have synthetic limits
as general applications for the preparation of unsymmetrical
R-bromoketones.
Table 2. Kinetic Bromination (Short Reaction Time)a
product (%)b
time
entry reactant (min) reactant internal terminal other
1
2
3
4
5a
6a
7a
8a
10
1
1
5a (3)
6a (6)
7a (8)
8a (0)
5b (87)
6b (80)
7b (75)
8b (100)
5c (1)
6c (5)
7c (7)
8c (0)
5e (9)
6e (9)
7d (6)
10
a
Reaction conditions: Br2 (1.0 equiv) was added, and acetic acid was
used as a solvent. b NMR integral ratio yield.
Figure 2. Compound list.
In this report, we have tried to discover a new synthetic
method for the preparation of R-bromoketones that are
brominated at the less activated terminal position of unsym-
Many reagents for reduction of R-bromoketones have been
3
developed: (i) reducing agents, e.g., zinc in acetic acid,
4
5
6
alkyltinhydride, vanadium(II) chloride, silicon hydride,
(
7) Goto, T.; Kishi, Y. Tetrahedron Lett. 1961, 513-515.
7
8
9
borohydride, stannous chloride, titanium(III) salts, sodium
(
8) Oriyama, T.; Mukaiyama, T. Chem. Lett. 1984, 2069-2070.
10
11
bisulfite, and benzimidazolines; (ii) nucleophilic reducing
(9) Clerici, A.; Porta, O. Tetrahedron Lett. 1987, 28, 1541-1544.
(10) Julian, P. L.; Karpel, W. J. J. Am. Chem. Soc. 1950, 72, 362-366.
12
13
agents, e.g., NaI/chlorotrimethylsilane, organophosphine,
(11) Chikashita, H.; Ide, H.; Itoh, K. J. Org. Chem. 1986, 51, 5400-
5
405.
(
2) Mehta, M. D.; Miller, D.; Tidy, D. J. D. J. Chem. Soc. 1963, 4614-
(12) Olah, G. A.; Arvanaghi, M.; Vankar, Y. D. J. Org. Chem. 1980,
4
616. Jones, E. R. H.; Wluka, D. J. J. Chem. Soc. 1959, 907-910. Mauli,
45, 3531-3532.
R.; Ringold, H. J.; Djerassi, C. J. Am. Chem. Soc. 1960, 82, 5494-5500.
(13) Borowitz, I. J.; Virkhaus, R. J. Am. Chem. Soc. 1963, 85, 2183-
2184.
Djerassi, C.; Finch, N.; Cookson, R. C.; Bird, C. W. J. Am. Chem. Soc.
1
960, 82, 5488-5493. Corey, E. J. J. Am. Chem. Soc. 1954, 76, 175-179.
(14) Clive, D. L. J.; Beaulieu, P. L. J. Org. Chem. 1982, 47, 1124-
Villotti, R.; Ringold, H. J.; Djerassi, C. J. Am. Chem. Soc. 1960, 82, 5693-
1126.
5
700. Corey, E. J. J. Am. Chem. Soc. 1953, 75, 4832-4834. Corey, E. J.
(15) Inoue, H.; Hata, H.; Imoto, E. Chem. Lett. 1975, 1241-1244.
(16) Seshadri, R.; Pegg, W. J.; Israel, M. J. Org. Chem. 1981, 46, 2596-
2598.
J. Am. Chem. Soc. 1953, 75, 3297-3299. Davies, A. R.; Summers, G. H.
R. J. Chem. Soc. 1967, 1227-1232.
(3) Corey, E. J.; Gregoriou, G. A. J. Am. Chem. Soc. 1959, 81, 3127-
(17) Ho, T.-L.; Wong, C. M. J. Org. Chem. 1974, 39, 562.
(18) Alper, H. Tetrahedron Lett. 1975, 2257-2260.
(19) Sargent, L. J.; Ager, J. H. J. Org. Chem. 1958, 23, 1938-1940.
(20) Pri-Bar, I.; Buchman, O. J. Org. Chem. 1985, 51, 734-736.
(21) Babadjamian, A.; Kessat, A. Synth. Commun. 1995, 25, 2203-2209.
Wyman, D. P.; Kaufman, P. R. J. Org. Chem. 1964, 29, 1956-1960.
Wyman, D. P.; Kaufman, P. R.; Freeman, W. R. J. Org. Chem. 1964, 29,
2706-2710. Rappe, C.; Sachs, W. H. J. Org. Chem. 1967, 32, 3700-3702.
3133. Zimmerman, H. E.; Mais, A. J. Am. Chem. Soc. 1959, 81, 3644-
3651.
(4) Kuivila, H. G.; Menapace, L. W. J. Org. Chem. 1963, 28, 2165-
2
167. Tanner, D. D.; Singh, H. K. J. Org. Chem. 1986, 51, 5182-5186.
(
5) Ho, T.-L.; Olah, G. A. Synthesis 1976, 807.
(6) Perez, D.; Greenspoon, N.; Keinan, E. J. Org. Chem. 1987, 52, 5570-
5
574.
12
4
Org. Lett., Vol. 5, No. 4, 2003

Table 3. Thermodynamic Bromination (Long Reaction Time)a
product (%)b
time
entry reactant
(h) reactant internal terminal
other
1
2
3
4c
5a
6a
7a
8a
24
3
3
5a (11)
6a (19)
7a (7)
5b (56)
6b (0)
7b (0)
5c (13) 5e (20)
6c (62) 6f (19)
7c (86) 7f (7)
8c (19) 8d (10)
Figure 3. Irreversible debromination with scavenger.
3
8a (17)
8b (45)
the nonselective 1,3-dibromination of phenylacetone as a
sample compound by 2 equiv of bromine, wherein 5e was
obtained as a major product and 5g was obtained as a minor
product, which also can be debrominated to 5c.
a
Reaction conditions: Br2 (1.0 equiv) was added, and acetic acid was
b
c
used as a solvent. NMR integral ratio yield. Yield of terminal product
c was increased by longer reaction times: after 16 h, 8a:8b:8c ) 3:3:2;
in addition, the solution was darkened, and some decomposition occurred.
8
metrical ketones. As the first step, to investigate the reactivity
of unsymmetrical ketones, two kinds of reaction conditions
were tested as shown in Tables 2 and 3. Brominations in
short reaction times (kinetically controlled) provided the
internally brominated compounds as a major product (Table
Table 5. Selective Preparation of Various Terminal Bromo
Compounds by the General Procedure, Including Nonselective
Bromination-Selective Debromination
2
1
2). However, Table 3 shows that brominations in longer
reaction times (thermodynamically controlled) gave the more
terminally brominated compound through the reversible
time1/
time 2 scavengera
isolated yield (%)b
26
reaction by Br
2
and produced hydrogen bromide. Although
reactant/Br
(equiv)
2
there were many reports on the rearrangement of R-bromo-
ketones, there were no reports on the selective preparation
of bromination in the less activated terminal position of
unsymmetrical ketones using this bromine rearrangement.
By controlling the reaction time, we could obtain 7c in an
acceptable yield, but the yields of the others (5c, 6c, and
(h/h)
(equiv)
reactant internal terminal other
a (2.2)c
5
6/30
2/30
0.5/1
3/0.5
A
5a (5)
5b (3)
5c (85) 5e (3)
6c (85) 6f (1)
7c (90) 7f (3)
8c (95) 8d (0)
6a (1.3)
7a (1.5)
H (0.6)
H (1.3)
A
6a (11) 6b (0)
7a (3)
8a (0)
7b (0)
8b (0)
8
a (2.0)d
a
b
Scavenger A ) acetone; scavenger H ) 1,4-hydrobenzoquinone. In
cases where acetone was used as a scavenger, byproduct that is thought to
be produced from bromoacetone makes separation by column chromatog-
raphy difficult; therefore, byproduct was removed by keeping the mixture
in vacuo for over 6 h. c Concentrated HBr was added. No addition of
8c) were not good.
d
concentrated HBr increases the amount of 5a. Product 8c is relatively stable
Table 4. 1,3-Dibromination of Phenylacetone (5a)a
product yield (%)
in an acidic reaction medium; however, after extraction, decomposition was
observed within 1 h.
reactant
temp
time
5b
5c
5e
5g
Consequently, several brominated compounds at the
terminal position were successfully prepared through the new
synthetic route shown in Scheme 1, and the results are shown
in Table 5. After 1,3-dibromination of the reactant by
addition of around 2 equiv of bromine and stirring for a long
time at room temperature, followed by addition of the
scavengers, the terminal bromo compounds were pro-
duced through the irreversibly selective debromination on
the internal bromides of the 1,3-dibromo compound as
shown in Figure 3. The scavenger was added after confirma-
tion of the disappearance of internal bromo compounds
5
5
5
a
a
a
rt
rt
80 °C
5 min
24 h
30 min
7.4
3.9
6.2
1.5
0.8
1.5
73.7
77.2
76.8
13.3
15.4
15.3
a
Reaction conditions: Br2 (1.0 equiv) was added, and acetic acid was
used as a solvent. NMR integral ratio yield. Yield of terminal product
c was increased by longer reaction times: after 16 h, 8a:8b:8c ) 3:3:2;
in addition, the solution was darkened and some decomposition occurred.
b
c
8
From the conjunction of the first and second discoVeries,
we designed a new synthetic route for the selective prepara-
tion of terminal bromocompounds composed of nonselective
bromination and selective debromination by hydrogen bro-
mide and a scavenger as shown in Scheme 1. Table 4 shows
(5b, 6b, 7b, and 8b), because (5b, 6b, 7b, and 8b) revert to
starting materials after debromination. In all of the cases,
the terminal compounds were obtained in more than 85%
yields. In the cases of 6a and 7a, internal bromo compounds
(
6b and 7b) were not detected when less than 2 equiv of
(
(
22) Calo, V.; Lopez, L.; Valentino, D. S. Synthesis 1978, 139-140.
23) Kageyama, T.; Tobito, Y.; Katoh, A.; Ueno, Y.; Okawara, M. Chem.
bromine were used.
Lett. 1983, 1481-1482.
24) Boyd, R. E.; Rasmussen, C. R.; Press: J. B. Synth. Commun. 1995,
5, 1045-1051.
25) Mignani, G.; Morel, D.; Grass, F. Tetrahedron Lett. 1987, 28, 5505-
508.
In conclusion, we discovered a new reducing system of
R-bromocarbonyl compounds using hydrobromic acid in the
presence of a scavenger of generated bromine. Using the
selective debromination, we could selectively prepare bromo
compounds that are brominated on the less activated R-posi-
(
2
5
5
(
(26) Kharasch, M. S.; Sternfeld, E.; Mayo, F. R. J. Am. Chem. Soc. 1937,
9, 1655-1657.
Org. Lett., Vol. 5, No. 4, 2003
413

tion of carbonyl from the mixture of polybrominated
compounds. This new method, bromination and selective
debromination, is useful because it is cheap and easy to use,
providing the selectively brominated product in high yields.
This method is useful for preparing 1-bromo-3-phenyl-
acetone, which cannot be prepared by either kinetically or
thermodynamically controlled reaction conditions and can
only be prepared by bromination following selective debro-
mination.
Acknowledgment. This work was supported by National
Research Laboratory Program, and we thank Dr. Choong
Eui Song for helpful discussions.
Supporting Information Available: Experimental pro-
cedures including characterization of all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0271638
414
Org. Lett., Vol. 5, No. 4, 2003