A new method for halogenation of aromatic compounds by using dimethyldioxirane and tetrabutylammonium halides

Article abstract of DOI:10.2174/157017809789869474

In this presentation the novel regioselective halogenation of arenes or phenols with dimethyldioxirane and Bu₄NX is described. The results showed that a new, versatile and mild method can be utilized for preparation of aryl halides starting with arenes or phenols. Finally, this aryl halide forming methodology is applicable to structurally more complex flavonoids.

Full text of DOI:10.2174/157017809789869474

Letters in Organic Chemistry, 2009, 6, 585-587
585
A New Method for Halogenation of Aromatic Compounds By Using
Dimethyldioxirane and Tetrabutylammonium Halides
Yean-Jang Lee*, Huan-Ting Wu and Chia-Ning Lin
Department of Chemistry, National Changhua University of Education, Changhua 50058, Taiwan
Received November 08, 2008: Revised August 11, 2009: Accepted August 11, 2009
Abstract: In this presentation the novel regioselective halogenation of arenes or phenols with dimethyldioxirane and
Bu4NX is described. The results showed that a new, versatile and mild method can be utilized for preparation of aryl
halides starting with arenes or phenols. Finally, this aryl halide forming methodology is applicable to structurally more
complex flavonoids.
Keywords: Dimethyldioxirane, regioselective halogenation, Bu4NX, flavonoids.
Aromatic halides are widely used substrates for a variety
of useful organic transformations, such as Ullmann [1],
Grignard [2], Heck [3], Stille [4], and Suzuki [5] reactions. A
number of common methods exist to prepare these
compounds, including (1) direct halogenation using Lewis
acid catalysts or strong oxidizing reagents to activate
elemental halogens, (2) preactivation by electrophilic
aromatic metallations with mercury, thallium, and boron, and
(3) Sandmeyer reactions, involving treatment of aryl
diazonium ions with halo-acids [6,7]. However, undesirable
characteristics of each of these methods limit their general
applicability. Recently, Mioskowsk [8] reported that
tetraethylammonium trichloride, prepared by passing
chlorine through a dichloromethane solution of tetraethyl-
ammonium chloride, acts as an arene chlorinating agent. In
addition, Fochi [9] has described a new method to prepare
aryl chlorides, bromides and iodides by treatment of stable
arenediazonium salts with tetraalkylammonium halides in
the presence of electron transfer catalysts. In spite of these
recent advances, the development of mild synthetic methods
that allow ready access to haloarenes is still a worthy
objective.
halogenation when reacted with DMD and Bu4NX. In
addition, we have found that phenols are converted to the
corresponding halides under these mild halogenation
conditions.
Insight into the scope of this reaction was initially gained
in studies with benzene derivatives 3a-c. Treatment of these
substances with 2 molar equivalents of DMD in 2 N HCl at -
30oC produces the corresponding chlorides 4a-c in yields
ranging from 70-76% (Scheme 2). Interesting results have
come from a study of the distribution of products arising
from reaction of the acetophenone derivative 3c with DMD
in the presence of varying concentrations of different acids.
For example, reaction of 3c with DMD in 0.05 N HCl yields
a mixture of phenol 5c and chloroacetophenone 4c in a 1:1
ratio. As expected, (1) phenol 5c is the sole product formed
in reaction of 3c with DMD in the absence of added acid,
and (2) neither 3c nor 5c react to form chlorobenzene 4c
when treated with 2 N HCl alone. In contrast, phenol 5c is
smoothly transformed into the corresponding chloride 4c in
91% yield when reacted with DMD in 2 N HCl. Moreover,
HBr and HF can be used in place of HCl in this process to
form the expected aryl bromide or fluoride, respectively. But
the reaction fails in this case when HI is used as the acid.
During the synthesis of kaempferol and its methylated
derivatives [10], we explored the use of a precedented
[11,12] dimethyldioxirane (DMD) promoted arene ring
hydroxylation reaction of flavone 1 (Scheme 1). In contrast
to [13] a recent report that aromatic ring hydroxylation
occurs when flavones are treated with DMD in 2 N HCl, we
observed that reaction of 1 under these conditions efficiently
yields the corresponding chloroflavone 2. In order to
determine the nature and scope of this novel reaction, we
examined alternative conditions under which the process
would occur and investigated its application to chlorination
of a number of simple and structurally complex arenes. In
this communication, we describe the results of this study
which show that aromatic compounds undergo efficient
In the course of exploring features of this novel
halogenation reaction, we found that tetrabutylammonium
halides can be used as the halogen sources. As shown in
Table 1, arenes 3a-c as well as benzoate ester 9 and
benzamide 10 are converted to aryl chlorides, bromides,
fluorides and iodides when reacted with DMD in acetone
solutions containing the corresponding tetrabutylammonium
halide salt (0.05~0.5 M) [14]. Likewise, phenols 5a-c are
readily transformed to the respective chlorides 4a-c when
treated with DMD and Bu4NCl. For instance, phenols 5a-c in
acetone are treated with 1 equiv. DMD and Bu4NCl
(0.05~0.5 M) to afford the corresponding chlorides 4a-c in
quantitative yield, respectively. Thus, it suggests that the
process of chloronation involves the intermediates 5a-c.
Finally, this procedure can not be used to directly halogenate
benzoic acids owing to the intervention of competing
decarboxylation (e.g., benzoic acid 11 reacts to form
chloroarene 4a under these conditions).
*Address correspondence to this author at the Department of Chemistry,
National Changhua University of Education, Changhua 50058, Taiwan;
Tel: 886-4-7232105 ext. 3511; Fax: 886-4-7211190;
E-mail: leeyj@cc.ncue.edu.tw
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

586 Letters in Organic Chemistry, 2009, Vol. 6, No. 7
Lee et al.
OMe
O
OMe
Cl
O
O
Cl
4 equiv. DMD
2 N HCl, -30 oC
(67%)
MeO
O
MeO
OMe
OMe
1
2
Scheme 1.
R2
Cl
R1
2 equiv. DMD
2 N HCl, -30 oC
(70-76%)
MeO
OMe
R2
4a (R1=R2=H)
4b (R1=COMe, R2=H)
R1
4c (R1=COMe, R2=OMe)
MeO
3a (R1=R2=H)
OMe
R2
HO
R1
1 equiv. DMD
3b (R1=COMe, R2=H)
-30 oC
3c (R1=COMe, R2=OMe)
MeO
5a (R1=R2=H)
OMe
(50-70%)
5b (R1=COMe, R2=H)
5c (R1=COMe, R2=OMe)
OMe
X
X
COMe
OMe
X
COMe
MeO
OMe
MeO
MeO
OMe
6a (X=Br)
6b (X=I)
7a (X=Br)
8a (X=Br)
8b (X=I)
8c (X=F)
7b (X=I)
7c (X=F)
COR
OMe
X
COR
MeO
MeO
OMe
9 (R=OMe)
10 (R=NEt2)
11 (R=OH)
11a (R=OMe, X=Cl)
11b (R=OMe, X=Br)
11c (R=OMe, X=I)
12 (R=NEt2, X=Br)
Scheme 2.
Table 1. Halogenations of Arene Promoted by Reaction with 2 Molar Equivalents of DMD in Acetone Solutions Containing Bu4NX
Arene
X in Bu4NX
Temp. (oC)
Product (Yield)
3a
3a
3a
3b
3b
3b
Cl
Br
I
0
0
4a (75%)
6a (79%)
6a (85%)
4b (85%)
7a (90%)
7b (70%)
25
0
Cl
Br
I
0
25

A New Method for Halogenation with DMD and Bu4NX
Letters in Organic Chemistry, 2009, Vol. 6, No. 7
(Table 1). Contd…..
Product (Yield)
587
Arene
X in Bu4NX
Temp. (oC)
3b
3c
3c
3c
3c
9
F
Cl
Br
I
0
0
7c (50%)
4c (76%)
8a (92%)
8b (78%)
8c (70%)
11a (74%)
11b (90%)
11c (78%)
12 (90%)
0
25
0
F
Cl
Br
I
0
9
0
9
25
0
10
Br
273, and references therein. McKillop, A.; Hunt, J.D.; Zelesko,
M.J.; Fowler, J.S.; Taylor, E.C.; McGillivray, Thiebes, C.; Prakash,
G.K.S.; Petasis, N.A.; Olah, G.A. Synlett, 1998, 141.
At this point, we do not know the detailed mechanism of
the new haloarene forming reaction. However, the results
accumulated, thus far, suggest that the process involves
initial precedented [11,12] hydroxylation of the aromatic
ring followed by DMD promoted halogen substitution at the
hydroxy center in the intermediate phenol [15]. In any event,
we have discovered a new, versatile and mild method for
preparation of aryl halides starting with arenes or phenols.
Mechanistic features of this process in addition to its scope
and limitations are issues being investigated in our
continuing studies in this area.
[7]
Obushak, M.D.; Lyakhovych, M.B.; Ganushchak, M.I.
Tetrahedron Lett., 1998, 39, 9567. Freedman, L.D.; Doak, G.O. J.
Org. Chem., 1965, 1263. Kajigaeshi, S.; Shinmasu, Y.; Fujisaki, S.;
Kakinami, T. Chem. Lett., 1989, 415. Boothe, R.; Dial, C.;
Conaway, R.; Pagni, R.M.; Kabalka, G.W. Tetrahedron Lett., 1986,
27, 2207. Banks, R.E.; Besheesh, M.K.; Mohialdin-Khaffaf, S.N.;
Sharif, I. J. Fluor. Chem., 1997, 81, 157. Fukui, K.; Nonaka, T.
Bull. Chem. Soc. Jpn., 1992, 65, 943. Hanson, P.; Jones, J.R.;
Gilbert, B.C.; Timms, A.W. J. Chem. Soc. Perkin Trans. 2, 1991,
1009. For an overview, see: Merkushev, E.B. Synthesis, 1988, 923.
Schlama, T.; Gabriel, K.; Gouverneur, V.; Mioskowski, C. Angew.
Chem. Int. Ed. Engl., 1997, 36, 2342.
[8]
[9]
Barbero, M.; Degani, I.; Dughera, S.; Fochi, R. J. Org. Chem.,
1999, 64, 3448.
ACKNOWLEDGEMENTS
[10]
[11]
Lee, Y.J.; Wu, T.D. J. Chin. Chem. Soc., 2001, 48, 201. Chu, H.W.;
Wu, H.T.; Lee, Y.J. Tetrahedron, 2004, 60, 2647.
Murray, R.W.; Jeyaraman, R. J. Org. Chem., 1985, 50, 2847.
Doering, W.von E.; Dorfman, E. J. Am. Chem. Soc., 1953, 75,
5595. Montgomery, R.E. ibid. 1974, 96, 7820. Adam, W.; Curci,
R.; Edwards, J.O. Acc. Chem. Res., 1989, 22, 205.
We thank the National Science Council of the Republic
of China (Research Grant NSC 96-2113-M-018-001-MY2
and NSC 89-2113-M018-016) for their financial support of
this research.
[12]
Adam, W.; Hadjiarapoglou, L.; Smerz, A. Chem. Ber., 1991, 124,
227. Tokunaru, H.; Kenichi, S.; Kazuyo, Y.; Yasuhiko, K.; Masao,
T. Chem.Pharm. Bull., 1997, 45, 446. Simakov, P.A.; Choi, S.Y.;
Newcomb, M. Tetrahedron Lett., 1998, 39, 8187. Murray, R.W.;
Singh, M.; Rath, N. ibid., 1996, 37, 8671. Bernini, R.; Mincione,
E.; Sanetti, A. ibid., 1997, 38, 4651.
REFERENCES
[1]
For recent reviews and references therein, see: Ullmann's
Encyclopedia of Industrial Chemistry, 6th ed.; Bailey, J.E.; Ed.;
John Wiley and Sons: New York, 1999. Ullmann, F. Ber. 1903, 36,
2389. Hennings, D.D.; Iwama, T.; Rawal, V.H. Org. Lett. 1999, 1,
1205. Fanta, P.E. Synthesis, 1974, 9. Hassan, J.; Penalva, V.;
Lavenot, L.; Gozzi, C.; Lemaire, M. Tetrahedron, 1998, 54, 13793.
Davies, I.W.; Matty, L.; Hughes, D.L.; Reider, P.J. J. Am. Chem.
Soc., 2001, 123, 10139.
[13]
[14]
Bernini, R.; Mincione, E.; Sanetti, A.; Mezzetti, M.; Bovicelli, P.
Tetrahedron Lett., 2000, 41, 1087.
The general procedure for the halogenation reaction is as follows:
the required volume of an acetone solution of DMD (0.01-0.05 M),
prepared according to method described by Adam [12] is added
rapidly to a cooled acetone solution of the arene containing
0.05~0.5 M Bu4NX. The course of the reaction is monitored by
TLC. After complete consumption of the substrate, solvent is
removed in vacuo and the residue obtained is subjected to column
chromatography on silica gel to give the corresponding haloarene
product. The structure of chloride 4 was identified by 1H, 13C NMR,
and GC Mass spectra, and compared with phenol 5.
[2]
[3]
For an overview and key references, see: Grignard Reagents: New
Developments; Richey, H.; Ed.; John Wiley and Sons: Chichester,
2000.
For recent reviews of the Heck reaction, see: Cabri, W.; Candiani,
I. Acc. Chem. Res., 1995, 28, 2. Crisp, G.T. Chem. Soc. Rev. 1998,
27, 427. Beletskaya, I.P.; Cheprakov, A.V. Chem. Rev., 2000, 100,
3009.
[15]
(a) A possible hint at the mechanism for the second step in the
sequence, involving phenol to chloroarene conversion, comes from
the proposal by Murray (ref. [15b]) that an SET pathway is
responsible for the DMD promoted isomerization of quadricyclane
to norbornadiene; (b) Murray, R.W. Chem. Rev., 1989, 89, 1187.
Mello, R.; Fiorentino, M.; Sciacovelli, O.; Curci, R. J. Org. Chem.,
1988, 53, 3890. Murray, R.W.; Pillay, M.K. Tetrahedron Lett.,
1988, 29, 15.
[4]
[5]
Stille, J.K. Pure Appl. Chem., 1985, 57, 1771. Stille, J.K. Angew.
Chem., Int. Ed. Engl., 1986, 25, 508. For recent reviews and
examples see: Farina, V.; Krishnamurthy, V.; Scott, W. J. Org.
React., 1997, 50, 1-652.
Miyamura, N.; Yanagi, T.; Suzuki, A. Synth. Commun., 1981, 11,
513. Suzuki, A. Pure Appl. Chem., 1991, 63, 419. Miyaura, N.;
Suzuki, A. Chem. Rev., 1995, 95, 2457. Moreno-Manas, M.; Perez,
M.; Pleixats, R. J. Org. Chem., 1996, 61, 2346. LeBlond, C.R.;
Andrews, A.T.; Sun, Y.; Sowa, J.R., Jr. Org. Lett., 2001, 3, 1555.
Sandmeyer, T. Chem. Ber., 1884, 1633. Zollinger, H. Diazo
Chemistry I; VCH Verlaggesellschaft mbH: Weinheim, 1994; Vol.
[6]