Hexabromoacetone and ethyl tribromoacetate: a highly efficient reagent for bromination of alcohol

Article abstract of DOI:10.1016/j.tetlet.2007.12.061

A new and efficient method for the bromination of alcohols utilizing Br₃CCOCBr₃/PPh₃ and Br₃CCO₂Et/PPh₃ is described. Various alcohols can be converted smoothly into their corresponding alkyl bromides in high yields under mild conditions with short reaction times. Based upon ¹H NMR studies using competitive reactions between selected brominating agents and Cl₃CCN, Br₃CCOCBr₃ displays the highest reactivity approximately nine times that of CBr₄.

Full text of DOI:10.1016/j.tetlet.2007.12.061

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1146–1148
Hexabromoacetone and ethyl tribromoacetate: a highly efficient
reagent for bromination of alcohol
Pratoomrat Tongkate, Wanchai Pluempanupat, Warinthorn Chavasiri *
Natural Products Research Unit, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
Received 4 February 2007; revised 1 December 2007; accepted 12 December 2007
Available online 7 January 2008
Abstract
A new and efficient method for the bromination of alcohols utilizing Br CCOCBr /PPh and Br CCO Et/PPh is described. Various
3
3
3
3
2
3
alcohols can be converted smoothly into their corresponding alkyl bromides in high yields under mild conditions with short reaction
1
times. Based upon H NMR studies using competitive reactions between selected brominating agents and Cl
displays the highest reactivity approximately nine times that of CBr4.
Ó 2007 Elsevier Ltd. All rights reserved.
3 3 3
CCN, Br CCOCBr
Keywords: Alcohols; Bromination; Hexabromoacetone; Ethyl tribromoacetate; Triphenylphosphine
The transformation of alkyl halides into valuable end
products is often utilized in organic syntheses. Alkyl chlo-
extended this idea for bromination and have examined
Br CCOCBr and Br CCO Et. Although Br CCOCBr
3
1
3
3
3
2
3
rides are often used since they are easily prepared using
readily available reagents such as SOCl , PCl or combined
was prepared in 1969, only two reports involving the syn-
thesis of bioactive compounds have been addressed. The
6
2
3
systems of PPh with CCl , Cl CCOCCl , Cl CCN or
preparation and the use of Br CCO Et for the preparation
3
4
3
3
3
3
2
2
7
Cl CCONH . However, alkyl chlorides are less reactive
of amides has also been described. Nonetheless, these two
reagents have never been reported as reagents for bromin-
ation of alcohols. Herein, we wish to report the use of
Br CCOCBr /PPh and Br CCO Et/PPh for the efficient
3
2
3
than alkyl bromides or iodides. Thus, an efficient and
practical protocol for the preparation of alkyl bromides
would be valuable. There are relatively few conditions for
the conversion of alcohols into bromides. Previous exam-
ples include highly toxic reagents such as HBr gas and
Br or coupling reagents like CBr /PPh , Br /PPh and
3
3
3
3
2
3
and practical conversion of alcohols into the corresponding
alkyl bromides and a relative reactivity study.
Conditions were optimized for the conversion of 2-phenyl-
ethanol into 2-phenylethyl bromide (Table 1).
2
4
3
2
3
Br PPh but HBr is always a by-product and high temper-
2
3
4
atures are often required.
Using a ratio of alcohol:brominating agent:PPh3 of
1:1.5:1.5 equiv, the desired product was obtained in low
to moderate yields in the case of BrCCl and Br CCO H
Recently, we have examined the reactivity of various
reagents for the chlorination of alcohols and carboxylic
3
3
2
5
acids to give the corresponding alkyl and acyl chlorides.
(entries 2 and 3). However, CBr , Br CCO Et and
4 3 2
The results clearly showed that the reagents possessing
strong electron-withdrawing groups such as Cl CCOCCl
Br CCOCBr afforded the bromide in excellent yields
3 3
(entries 4, 7 and 10). Interestingly, decreasing the amount
of Br CCO Et and Br CCOCBr from 1.5 to 1 and
3
3
and Cl CCN showed the highest reactivity. We have now
3
3
2
3
3
0.3 equiv, respectively, still provided the desired bromide
in quantitative yields (entries 8, 9 and 11–14). Moreover,
a short reaction time (15 min) also gave the alkyl bromide
in excellent yields (entries 8 and 13).
*
Corresponding author. Tel.: +66 2 2187625; fax: +66 2 2187598.
E-mail address: warintho@yahoo.com (W. Chavasiri).
0
040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.061

P. Tongkate et al. / Tetrahedron Letters 49 (2008) 1146–1148
1147
Table 1
Effect of the types of brominating agent, ratio of brominating agent and
PPh and reaction time on the conversion of 2-phenylethanol into 2-
phenylethyl bromide
Table 2
Bromination of alcohols
3
PPh (1.5 eq)
Brominating agent
3
ROH
PPh (1.5 eq)
RBr
3
0
.25 mmol CH Cl , RT, 15 min
2 2
Brominating agent
OH
Br
Ph
0
Ph
a
b
Entry Alcohol
Brominating agent
Yield (%)
CH Cl , RT, 30 min
2
2
.25 mmol
RBr Olefin
a
Entry
Brominating agent
Yield (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
a
1-Octanol
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
CCOCBr
3
3
3
97
Quant
98
—
—
—
—
—
—
—
—
—
15
12
—
—
30
48
CCO
CCO
2
Et
Et
Type
None
Amount (equiv)
Phenylmethanol
2-Phenylethanol
2
1
2
3
—
1.5
1.5
0
21
c,d
CCOCBr
98, 83
98, 82
b
BrCCl
Br CCO
3
c,d
CCO
CCO
2
Et
Et
3
2
H
42
c,d
(À)-Nopol
2
78
(± )-2-Octanol
CCOCBr
Quant
97
98
4
5
6
CBr
4
1.5
1.0
0.5
96
90
42
CCO
CCO
2
Et
Et
(± )-1-Phenylethanol
Cyclooctanol
2
1
1
1
1
1
1
CCOCBr
CCO Et
CCOCBr
CCO Et
CCOCBr
CCO Et
3
3
3
84
2
87
7
8
9
Br
Br
3
CCO
2
Et
1.5
1.0
0.5
95
c,d
1-Adamantanol
42
c,d
c
96, 98
2
48
78
2-Phenyl-2-propanol Br
Br
67
42
2
1
1
1
1
1
0
1
2
3
4
a
3
CCOCBr
3
1.5
1.0
0.5
0.3
0.25
98
99
99
0
.3 equiv Br
3
CCOCBr
3
was used; 1 equiv Br
3
2
CCO Et was used.
b
1
Determined by HNMR.
Isolated product.
mmol of ROH was used.
c
c
99, 98
d
3
74
1
Determined by H NMR.
-Phenylethyl chloride was also obtained in 40% yield.
Reaction time was 15 min.
b
c
2
2e
rination of cyclooctanol using Cl CCONH /PPh . The
3
2
3
present results indicate that bromide is a more reactive
nucleophile than chloride to generate the corresponding
This optimized reaction conditions were utilized in a
cyclic halides via S 2 displacement. Tertiary alcohols gave
N
study on the scope of bromination of various primary, sec-
ondary and tertiary alcohols (Table 2).
the corresponding alkyl bromides in poorer yields (entries
12–15). This implies that the reaction may take place via
two competing pathways, substitution versus elimination.
All the primary and secondary, alkyl and cyclic alcohols
studied were converted into the corresponding alkyl bro-
mides in high to excellent yields using Br CCO Et or
Br
Br
CCOCBr
CCO
was a more efficient brominating agent than
Et for tertiary alcohols (entries 14 and 15).
2
3
3
3
3
2
Br CCOCBr (entries 1–11). An olefinic by-product was
The reactivity of various reagents in the bromination of
alcohols to bromides was also investigated using a compet-
itive reaction between Cl CCN and various brominating
agents towards 2-phenylethanol (Table 3).
3
3
detected as a minor component from 1:5.60 to 1:7.25
entries 10 and 11). The formation of an olefinic by-prod-
(
3
8
uct in a ratio of 1:1.40 was previously observed in the chlo-
Table 3
Comparative reactivity study of brominating agents
PPh (1.5 eq)
3
Cl CCN (0.75 eq)
3
Brominating agent (0.75 eq)
Ph
Ph
+
Ph
OH
Br
Cl
CH Cl , RT, 15 min
2
2
a
b
Entry
Brominating agent
None
Yield (%)
Ratio of Br/Cl
Reactivity
Br
Cl
1
2
3
4
5
a
0
32
40
47
80
76
65
60
52
18
—
—
1
1.37
1.84
9.06
CBr
4
0.49
0.67
0.90
4.44
Br
3
Br
3
Br
3
CCO
CCONEt
CCOCBr
2
Et
2
3
1
Determined by H NMR.
b
4
Based on CBr .

1148
P. Tongkate et al. / Tetrahedron Letters 49 (2008) 1146–1148
In the absence of brominating agent, 2-phenylethyl chlo-
ride was obtained in high yield (entry 1). Br CCO Et dis-
tive program (KO 47/2547) and the Graduate school,
Chulalongkorn University.
3
2
played reactivity close to those of CBr and Br CCONEt
2
4
3
(
entries 2 and 3). Intriguingly, Br CCOCBr , bearing a
References and notes
3
3
strong electron-withdrawing group, significantly displayed
the highest reactivity (entry 5). The highest reactivity was
associated with the strongest electron-withdrawing groups,
1
. (a) Gawande, M. B.; Deshpande, S. S.; Satam, J. R.; Jayaram, R. V.
Catal. Commun. 2007, 8, 576–582; (b) Gonzalez-Bobes, F.; Fu, G. C. J.
Am. Chem. Soc. 2006, 128, 5360–5361; (c) Kamal, A.; Chouhan, G.
Tetrahedron Lett. 2005, 46, 1489–1491.
5
just as was observed for chlorination.
In summary, we have disclosed an efficient method for
the preparation of alkyl bromides from alcohols using
Br CCOCBr /PPh or Br CCO Et/PPh .
A typical procedure for the preparation of an alkyl bro-
mide: To a stirred solution of alcohol (0.25 mmol) and
2
. (a) Caserio, F. C.; Dennis, G. E.; Dewolfe, R. H.; Young, W. G. J. Am.
Chem. Soc. 1955, 77, 4182–4183; (b) Susan, D. T.; Joyce, T. D. J. Org.
Chem. 1987, 52, 4999–5003; (c) Magid, R. M.; Talley, B. G.; Souther,
S. K. J. Org. Chem. 1981, 46, 824–825; (d) Matveeva, E. D.; Kurts, A.
L.; Yalovskaya, A. I.; Nikishova, N. G.; Bundel, Y. G. Zh. Org. Khim.
3
3
3
3
2
3
1
989, 25, 652–653; (e) Pluempanupat, W.; Chavasiri, W. Tetrahedron
PPh3 (0.375 mmol) in dry CH Cl (0.5 mL) was added
2
2
Lett. 2006, 47, 6821–6823.
Br CCO Et (0.25 mmol) or Br CCOCBr (0.075 mmol) at
3. Munbunjong, W.; Lee, E. H.; Chavasiri, W.; Jang, D. O. Tetrahedron
Lett. 2005, 46, 8769–8771.
3
2
3
3
rt (30 °C) under a N atmosphere. After 15 min, the reac-
2
4
. (a) Meyers, C. Y.; Hou, Y.; Lutfi, H. G.; Saft, H. L. J. Org. Chem.
tion was quenched with cold water and the presence of
the corresponding product in the crude mixture was deter-
1
999, 64, 9444–9449; (b) Deno, N. C.; Potter, N. H. J. Am. Chem. Soc.
967, 89, 3555–3556; (c) Wagner, A.; Heitz, M. P.; Mioskowski, C.
1
1
mined by H NMR analysis utilizing toluene as an internal
Tetrahedron Lett. 1990, 31, 3141–3144; (d) Schaefer, J. P.; Higgins, J. J.
Org. Chem. 1967, 32, 1607–1608; (e) Wiley, G. A.; Hershkowitz, R. L.;
Rein, B. M.; Chung, B. C. J. Am. Chem. Soc. 1964, 86, 964–965.
. Pluempanupat, W.; Chantarasriwong, O.; Taboonpong, P.; Jang, D.
O.; Chavasiri, W. Tetrahedron Lett. 2007, 48, 223–226.
. (a) Gilbert, E. E. Tetrahedron 1969, 25, 1801–1806; (b) Sato, A.;
Sugano, M.; Horikoshi, H.; Yoshioka, S.; Nagaki, H. J.P. 02,145,541,
1990; Chem. Abstr. 1990, 113, 178250.; (c) Kawanishi, S. J.P.
standard or alternatively was isolated by purification
through silica gel column chromatography.
5
6
A reactivity study: To a stirred solution of alcohol
(
(
(
0.25 mmol) and
0.188 mmol) and Cl CCN (0.188 mmol) in dry CH Cl
2
a
mixture of brominating agent
3
2
0.5 mL) was added PPh (0.375 mmol) at rt (30 °C) under
3
3
3,007,980, 1958; Chem. Abstr. 1960, 54, 28884.
a N atmosphere. After 15 min, the amount of the corres-
2
7
. (a) Chaysripongkul, S. Master’s Thesis, Department of Chemistry,
Chulalongkorn University, 2003; (b) Kang, D. H.; Joo, T. Y.; Lee, E.
H.; Chaysripongkul, S.; Chavasiri, W.; Jang, D. O. Tetrahedron Lett.
ponding products in the crude mixture was determined
1
by H NMR analysis using toluene as an internal standard.
2
006, 47, 5693–5696; (c) Kang, D. H.; Joo, T. Y.; Chavasiri, W.; Jang,
Acknowledgements
D. O. Tetrahedron Lett. 2007, 48, 285–287.
. The reactivity of the brominating agents was assessed by the ratio of
the yields of 2-phenylethyl bromide and 2-phenylethyl chloride
obtained.
8
This work was financially supported by a joint research
project under the NRCT-KOSEF international coopera-