1
384
S. R. K. Pingali et al. / Tetrahedron Letters 51 (2010) 1383–1385
Table 1
Table 2
Isolated yields of mono-brominated arenes24,25
Non-selective bromination in the ionic liquid
R
4
R
5
R
4
R
5
R
4
Br
R4
R1
Br
R4
NBS
NBS
R
3
R
3
Br
R
3
R3
+
R3
Br
[
Bmim]Br
[bmim]Br
R
2
R
1
R
2
2
R
1
R
2
R
1
R2
R2
R1
2
3
4
5
1
a: R
1
= R
2
= R
4
= R
5
= H, R
3
= NH
2
; b: R
1
= R
= R
4
= R
5
= H, R
3
= OH;
a: R
1
= OH, R
2
= CHO, R
3
= R
4
= H; b: R
1
= OH R
2
= COOH, R
3
4
= R = H;
c: R1 = R2 = R4 = R5 = H, R3 = OCH ; d: R = R2 = R4 = R5 = H, R3 = N(CH ) ;
c: R1 = R3 = H; R4 = OH, R2 = COOH; d: R1 = R3 = H; R4 = OH, R2 = COOH;
3
1
3 2
= NO
e: R
g: R
i: R
1
= NH
= R
= CHO, R
2
, R
= H, R
= R
2
= R
= R
= R
3
= R
= CH
= H, R
5
= H, R
4
= NO
2
; f: R
1
= OH, R
= R = H, R
; j: R
= (CH N, R
2
= R
= CHO, R
= R = R
3
= R
5
= H, R
= OCH
= H, R
4
2
;
e: R
1
= NH
= NH
2
, R
2
= COOH, R
3
= R
4 1 3 4 2
= H; f: R = R = H; R = NH2, R = COOH;
, R
2
= CN, R = R
3
4
1
5
2
4
3
; R
3
= OH; h: R
= OCH
1
5
2
3
3
;
g: R
1
2
= H
1
2
4
5
3
3
1
3
)
2
2
3
5
4
= CHO
Product
Time (min)
Conversion (%)
Mono/di (ratio)
Compound
Ionic liquid/dioxane
Time (min)
Isolated Yield (%)
Selectivity (%)
4
4
4
4
4
4
4
a/5a
b/5b
c/5c
d/5d
e/5e
f/5f
2
2
3
2
5
4
2
80
65
85
100
50
100
70
2/3
2/3
2/3
1/4
1/4
2/3
2/3
2
2
2
2
2
2
2
2
2
2
a
b
c
d
e
f
g
h
i
5/5
5/5
8/5
5/1
4/2
5/2
2/1
15/5
15/5
5/4
85/91
75/75
93/95
95/95
90/80
85/75
98/95
95/80
93/85
90/78
100/100
100/80
100/100
100/100
100/100
95/80
100/100
100/100
100/95
g/5g
2
NH is required to facilitate these substrates bromination products.
At the present time we do not have plausible explanation for out-
come of this reaction.
j
100/100
We also utilized different solvents through the course of our
studies, to determine what, if any, changes would occur in the reg-
ioselectivity or isolated yields of our bromination products. There-
fore, we compared the ionic liquid/NBS-facilitated aromatic
bromination with NBS/dioxane bromination. Using a bromine–
dioxane complex for aromatic bromination is well documented.12
Recently, NBS aromatic bromination in the presence of polyethyl-
of the product was higher than 96%. However, it is important to
emphasize that the ionic liquid must be dried to obtain these high
yields. Commercially available [Bmim]Br must be dried under vac-
uum prior to use in these reactions. The presence of water substan-
tially decreases both the isolated yield and the selectivity of the
aromatic bromination.
2
3
ene glycol suggests the possibility to utilize NBS-dioxane for aro-
matic bromination. Using this reagent mixture, we obtained
excellent monobromination for phenol and aniline (Table 1). The
isolation procedure following this reaction is exceptionally simple
and the results were comparable to the ionic liquid-mediated bro-
mination. However, when phenol and aniline derivatives with
strong electron-withdrawing groups such carboxylic, nitro, formyl,
and cyano were brominated, a complex mixture of mono- and di-
bromo products.
In conclusion, it can be stated that a new, very efficient aromatic
bromination method was developed for bromination active aro-
matic compounds. Para monobromination was accomplished in a
few minutes by using NBS as a safe bromine source and an ionic
liquid as a recyclable reaction medium. It is necessary to micro-
wave the ionic liquid prior to its use or reuse in the bromination
process to activate the ionic liquid. The selectivity and isolated
yield are almost identical after five times recycling of the ionic li-
quid. Furthermore, the reaction is also applicable to large scale aro-
matic bromination.
To eliminate this problem of extensively drying the ionic liquid
prior to use, we implemented microwave activation of the ionic li-
quid prior to reactions. The ionic liquid was microwaved for 15 s at
microwave powers of 150 W prior to being added to the reaction
mixture as a reagent. Alternatively, we have also prepared
Bmim]Br from 1-methylimidazole and butyl bromide.22 In this
[
case, the ionic liquid was used immediately after its preparation
without drying. After bromination was completed (Table 1) the
product (together with succinimide) was extracted from ionic
liquid with ether. The remaining ionic liquid was microwaved at
1
50 W for 15 s and reused. We repeated the same reaction of
bromination of phenol five times with recycling the ionic liquid
without loss of selectivity or decreased isolated yield of 4-bromo-
phenol. In addition, an additional reaction was performed on a
large scale (10 g of anisole) with almost quantitative yield (97%)
of 4-bromoanisole.
Bromination of benzene with one hydroxyl, amino, N,N-dimeth-
ylamino, or methoxy groups produced the single 4-brominated
product in almost quantitative yield (Table 1, compounds 2a–d).
For N,N-dimethylaniline and anisole, the presence of an aldehyde,
nitro, or carboxylic group did not change the outcome of the reac-
tion nor the reaction time. Bromination occurred selectively in the
para position with regard to the activating aromatic substituent
Acknowledgment
We thank the National Science Foundation for financial support
(
CHE-0611902) for this work.
(Table 1, compounds 2f–k). Interestingly, for phenol and aniline
with a carboxylic acid, aldehyde, or cyano group, the formation
of the dibromo product is preferred over monobromo product (Ta-
ble 2). We were not able to perform selective monobromination
even when less than one equivalent of NBS was used. One can ar-
gue that the OH group is stronger aromatic activating group than
References and notes
1.
Szmant, H. H. Organic Building Blocks of the Chemical Industry; Wiley: New York,
1989.
2. Stanforth, S. P. Sci. Synth. 2007, 31a, 121–160.
3.
For instance: (a) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534–1544; (b)
McGlacken, G. P.; Bateman, L. M. Chem. Soc. Rev. 2009, 38, 2447–2464; (c)
Brennfuehrer, A.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed. 2009, 48, 4114–
4133; (d) de Meijere, A.; Stulgies, B.; Albrecht, K.; Rauch, K.; Wegner, H. A.;
Hopf, H.; Scott, L. T.; Eshdat, L.; Aprahamian, I.; Rabinovitz, M. Pure Appl. Chem.
3
OCH and therefore, this might be an explanation for the ease of
dibromination in these substrates. However, the same was not
found for phenol and aniline, where the only product detected
was the 4-bromophenol and 4-bromoaniline products, respec-
tively. Based on our observations, we hypothesize that the pres-
ence of electron-withdrawing group in combination with OH or
2006, 78, 813–830.
4.
(a) De La Mare, P. B. D. Electrophilic Halogenation: Reaction Pathways Involving
Attack by Electrophilic Halogens on Unsaturated Compounds; Cambridge