Direct conversion of bromohydrins to ketones by a free radical elimination of hydrogen bromide

Article abstract of DOI:10.1021/jo016113y

Secondary β-bromo alcohols can be transformed directly to ketones in very good yields by a free radical process. Tertiary β-bromo alcohols do not react while the primary ones are transformed to aldehydes in lower yields. The reaction involves an abstraction of a hydrogen atom α to an OH group, followed by elimination of the bromine atom and subsequent tautomerization of an enol to a ketone.

Full text of DOI:10.1021/jo016113y

3
12
J . Org. Chem. 2002, 67, 312-313
Dir ect Con ver sion of Br om oh yd r in s to
Sch em e 1
Keton es by a F r ee Ra d ica l Elim in a tion of
Hyd r ogen Br om id e1
Darko Dolenc* and Maja Harej†
Faculty of Chemistry and Chemical Technology, University
of Ljubljana, A sˇ ker cˇ eva 5, SI-1000 Ljubljana, Slovenia
Ta ble 1. Rea ction s of Br om oh yd r in s a n d DBP O in
Cycloh exa n ea
darko.dolenc@uni-lj.si
Received September 13, 2001
Abstr a ct: Secondary â-bromo alcohols can be transformed
directly to ketones in very good yields by a free radical
process. Tertiary â-bromo alcohols do not react while the
primary ones are transformed to aldehydes in lower yields.
The reaction involves an abstraction of a hydrogen atom R
to an OH group, followed by elimination of the bromine atom
and subsequent tautomerization of an enol to a ketone.
Few procedures for direct transformation of halohy-
drins to carbonyl compounds have appeared in the lit-
erature. Most of them are based on reactions of halohy-
2
drins with bases and/or acids or transition metal cata-
3
lysts. More recently, a photochemical transformation of
bromohydrins to ketones in benzene or toluene was
4
reported. In our study of reactions of organic halogen
5
compounds with radicals, we have observed that bro-
mohydrins eliminate hydrogen bromide in a free radical
process, yielding ketones (Scheme 1).
Heating a mixture of trans 2-bromocyclohexanol and
6
di-tert-butyl peroxyoxalate (DBPO) in cyclohexane at
6
0-80 °C for a few minutes resulted in the formation of
cyclohexanone in quantitative yield (see Table 1). White
fumes of hydrogen bromide were also observed over the
reaction mixture. Other secondary â-bromo alcohols
reacted likewise. On the contrary, chloro and iodo ana-
logues reacted differently. Under the same reaction
conditions, trans 2-chlorocyclohexanol remained almost
unreacted, yielding only trace amounts of cyclohexanol.
The reaction of trans 2-iodocyclohexanol resulted mainly
in deiodination, thus leading to the formation of cyclo-
hexanol, accompanied by a small amount of cyclohex-
anone.
Tertiary â-bromo alcohols did not react at all; however,
with primary bromohydrins, aldehydes were formed in
relatively low amounts, probably due to further reactions.
A pure aliphatic bromohydrin, 2-bromooctan-1-ol, yielded
a
0.2 mmol of halohydrin and 0.06 mmol of DBPO in 2 mL of
b
c
cyclohexane, 60 °C to reflux, 10 min. Determined by GC. Iso-
lated yield on 2 mmol scale. d Polymer. e 55% of acetophenone was
also formed.
6
1% of aldehyde, while 2-bromo-2-phenylethanol only
gave tarry products.
†
Undergraduate student.
(
1) Presented in part at the National meeting Slovenski kemijski
dnevi 2000, Maribor, Slovenia, September 2000. Book of abstracts, p
2.
Elimination appeared to be severely affected by the
solvent. The highest conversions and yields of ketones
were obtained in cyclohexane and benzene. Conversions
were significantly lower in other solvents (acetone, ace-
tonitrile, AcOH); in those which are good hydrogen atom
donors (EtOH, toluene, THF), the reaction did not take
place at all.
The reaction seems to be initiated by the abstraction
of the R-hydrogen atom from a halo alcohol by an
electrophilic radical, which yields a stabilized R-hydroxy-
7
(2) Tiffenau, M. Bull. Soc. Chim. Fr. 1945, 12, 621. Geissman, T.
A.; Akawie, R. I. J . Am. Chem. Soc. 1951, 73, 1993. Hussey, A. S.;
Herr, R. R. J . Org. Chem. 1959, 24, 843. Sisti, A. J .; Vitale, A. C. J .
Org. Chem. 1972, 37, 4090.
(3) Tsuji, J .; Nagashima, H.; Sato, K. Tetrahedron Lett. 1982, 23,
3
085.
(
(
(
4) Piva, O. Tetrahedron Lett. 1992, 33, 2459.
5) Dolenc, D.; Plesni cˇ ar, B. J . Am. Chem. Soc. 1997, 119, 2628.
6) Bartlett, P. D.; Benzing, E. P.; Pincock, R. E. J . Am. Chem. Soc.
1
960, 82, 1762.
1
0.1021/jo016113y CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/08/2001

Notes
Sch em e 2. P r op osed Mech a n ism of Hyd r ogen
J . Org. Chem., Vol. 67, No. 1, 2002 313
corresponding epoxides with 48% HBr in diethyl ether (com-
pounds 1a -3a , 6a , and 8a ).11 2-Chloro- and 2-iodocyclohexanol
were prepared from cyclohexene oxide and the corresponding
acid. Spectral and/or other data for halohydrins are reported
elsewhere.1
Br om id e Elim in a tion fr om Br om oh yd r in s
0,12-17
2
-Br om o-3-h yd r oxy-3-p h en ylp r op yl Aceta te (9a ). A total
of 2.0 mmol of (E)-3-phenylprop-2-en-1-yl acetate was added
dropwise to the stirred solution of N-bromosaccharin (2.0 mmol)
in 4 mL of acetonitrile-water mixture (3:1 v/v). The reaction
mixture was stirred at room temperature for 1 h, diluted with
diethyl ether, washed with sodium hydrogen carbonate and
water, dried over anhydrous sodium sulfate, and concentrated
in vacuo. The crude product was purified by chromatography
(
3
silica gel, CH
-phenylpropyl acetate as a white solid which was recrystallized
from CH Cl /hexane, mp 45-46 °C. The crystallized compound
contains one molecule of water, otherwise it is an oil. H NMR
CDCl , δ/ppm): 2.02 (s, 3H), 4.33 (dd, J ) 11.5, 4.1 Hz, 1H),
2 2
Cl ) to afford 151 mg (55%) of 2-bromo-3-hydroxy-
alkyl radical that in turn eliminates a â-halogen atom,
thus forming a double bond (Scheme 2).
2
2
1
This process is feasible only in the case of bromohy-
drins since the enthalpy of a π-bond formation is com-
(
4
3
.44 (m, 1H), 4.52 (dd, J ) 11.5, 6.6 Hz, 1H), 5.01 (d, J ) 6.1
7
parable with C-Br bond dissociation energy. In chloro-
Hz, 1H), 7.35 (m, 5H). 13C NMR (CDCl , δ/ppm): 20.6, 55.5, 64.2
3
+
hydrins, the C-Cl bond is considerably stronger, causing
the elimination of a chlorine atom to be unfavorable. In
iodohydrins, a competing abstraction of iodine atom
predominates, at least in solvent cyclohexane, where
nucleophilic cyclohexyl radicals are present.
74.9, 126.4, 128.3, 128.5, 139.5, 170.8. MS (EI): 274 (M + 2,
+
0
.8), 272 (M , 0.8), 193 (5), 149 (10), 133 (62), 107 (100), 105
(
63), 91 (17), 79 (45), 77 (32). Anal. Calcd for C11
H
13BrO
3
2
‚xH O:
C, 45.38; H, 5.19. Found: C, 45.29; H 5.43.
1
-(3-Tr iflu or om eth ylp h en yl)-2-br om oeth a n ol. Oil (57%).
1
H NMR (CDCl , δ/ppm): 3.53 (dd, J ) 10.6, 8.7 Hz, 1H), 3.66
3
The nature of the hydrogen abstracting radical is
obviously electrophilic, in this case tert-butoxy radical or
bromine atom. A Hammett plot for the elimination of
HBr from substituted 1-aryl-2-bromoethanols (3-trifluo-
romethyl, H and 4-methyl) shows a linear correlation
with F ) -1.0, which is comparable to, for example,
(dd, J ) 10.6, 3.4 Hz, 1H) 5.00 (dm, J ) 8.5 Hz, 1H) 7.48-7.68
ppm (m, 4H). 13C NMR (CDCl
, δ/ppm): 39.7, 73.1, 122.9, 124.0
3
(
q, J ) 272 Hz), 125.2, 129.2, 129.4, 131.1 (q, J ) 32 Hz), 141.5.
1
9
+
F NMR (CDCl
3
, δ/ppm (CFCl
3
)): -63.2 (s). MS (EI): 270 (M
+
+
2, 0.2), 268 (M , 0.2), 175 (100), 159 (8), 145 (16), 127 (50).
Anal. Calcd for C
H, 2.89.
9 8 3
H BrF O: C, 40.18; H, 3.00. Found: C, 39.90;
8
bromination of toluene. Moreover, a nucleophilic alkyl
Products were identified by NMR and/or GC-MS and data
were compared with those of authentic materials or literature.
Elim in a tion s: Gen er a l P r oced u r e. A total of 0.2 mmol of
bromohydrin and 0.03 mmol of DBPO were dissolved in 2 mL
of cyclohexane and placed in a flask, fitted with a reflux
condenser. The solution was purged with argon and warmed in
a water bath gradually from about 50 °C to reflux, during 15
min, and left at reflux for additional 10 min. The composition
of the reaction mixture was then analized by GC. In preparative
runs (2 mmol of bromohydrin, 0.3 mmol of DBPO in 5 mL of
cyclohexane) the reaction mixtures were diluted with ether,
washed with sodium hydrogen carbonate and water, and dried
with anhydrous sodium sulfate and the solvent was evaporated
under reduced pressure.
radical would most probably abstract a halogen atom
rather than an R-hydrogen.
In certain cases we have observed a minor side reac-
tion, namely the formation of a 2-bromoketone, which
could be formed by the abstraction of a hydroxyl hydrogen
atom from R-hydroxyalkyl radical by a bimolecular
radical process and could therefore be suppressed by
working at lower temperature. The most efficient proce-
dure was found to be the warming of the reaction mixture
in a water bath starting at 50-60 °C to reflux (of
cyclohexane) during 15 min. In preparative runs or in
cases of acid sensitive compounds, the reaction mixture
was continuously purged with inert gas during the course
of reaction.
The most suitable radical initiator proved to be di-tert-
butyl peroxyoxalate, since it is a clean source of alkoxyl
radicals. Initiation with dibenzoyl peroxide led to the
formation of a complex mixture. The amount of initiator
necessary for complete conversion is variable, but in most
cases 10-20 mol % (based on the starting bromohydrin)
is adequate.
Rela tive Ra tes of Elim in a tion of HBr fr om Su bstitu ted
1-P h en yl-2-br om oeth a n ols. A solution of substituted 2-bromo-
1
ethanol (0.2 mmol), and DBPO (0.01 mmol) in 2 mL of cyclo-
hexane was purged with argon, warmed as described above, and
3 3
-phenylethanol (4-CH , 3-CF , 0.2 mmol), 2-bromo-1-phenyl-
analyzed by GC. The relative rates k
the integrated rate equation k /k ) ln(A/A
is the amount of substituted bromohydrin and B is the amount
of unsubstituted bromohydrin at the end of the reaction. A and
are the amounts of bromohydrins at the begining of the
X
/k
H
were calculated using
X
H
o
)/ln(B/B ), where A
o
o
B
o
reaction. The measurement was made as a one-point kinetic
determination and the values thus obtained are: k(4-Me)/k(H)
)
The reaction may suggest a new efficient way for
conversion of bromohydrins or, indirectly, even alkenes
to ketones and is also successful with acid or base
sensitive compounds, such as esters.
1.52 and k(3-CF
3
)/k(H) ) 0.38.
J O016113Y
(10) Dalton, D. R.; Dutta, V. P.; J ones, D. C. J . Am. Chem. Soc. 1968,
9
4
0, 5498.
Exp er im en ta l Section
(11) Chini, M.; Crotti, P.; Gardelli, C.; Macchia, F. Tetrahedron 1992,
8, 3805.
(12) Masuda, H.; Takase, K.; Nishio, M.; Hasegawa, A.; Nishiyama,
Gen er a l. Bromohydrins 4a , 5a , 7a , 9a , and 10a were
synthesized from alkenes and NBS or, preferably, N-bromosac-
Y.; Ishii, Y. J . Org. Chem. 1994, 59, 5550.
9
10
(13) Caputo, R.; Ferreri, C.; Noviello, S.; Palumbo, G. Synthesis 1986,
, 499.
charin in aqueous acetonitrile or DMSO or by the reaction of
6
(
14) Kraus, G. A.; Gottschalk, P. J . Org. Chem. 1983, 48, 2111.
(
7) CRC Handbook of Chemistry and Physics, 76th ed.; Lide, D. R.,
(15) Cowell, A.; Stille, J . K.; J . Am. Chem. Soc. 1980, 102, 4193.
(16) Traynham, J . G.; Schneller, J . J . Am. Chem. Soc. 1965, 87, 2398.
(17) Wilson, M. A.; Woodgate, P. D. J . Chem Soc., Perkin Trans. 2
Ed.; CRC Press: Boca Raton, 1995.
(
(
8) Amey, R. L.; Martin, J . C. J . Am. Chem. Soc. 1979, 101, 3060.
9) Zajc, B. Synth. Commun. 1999, 29, 1779.
1976, 141.