Selective bromination of dehydroacetic acid with N-bromosuccinimide

Article abstract of DOI:10.1080/00397911.2011.566461

(Chemical Equation Presented) Bromination of dehydroacetic acid has been carried out with N-bromosuccinimide under various conditions. The reactions led to selective bromination, thereby offering efficient synthesis of 3β-bromodehydroacetic acid (3), 3β,5

Full text of DOI:10.1080/00397911.2011.566461

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Selective Bromination of Dehydroacetic
Acid with N-Bromosuccinimide
Ajay Kumar a , Poonam Lohan b & Om Prakash a
a Institute of Pharmaceutical Sciences, Kurukshetra University,
Kurukshetra, India
b Department of Chemistry, Kurukshetra University, Kurukshetra,
India
Accepted author version posted online: 31 Oct 2011.Version of
record first published: 29 May 2012.
To cite this article: Ajay Kumar, Poonam Lohan & Om Prakash (2012): Selective Bromination of
Dehydroacetic Acid with N-Bromosuccinimide, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 42:18, 2739-2747
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Synthetic Communications1, 42: 2739–2747, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.566461
SELECTIVE BROMINATION OF DEHYDROACETIC ACID
WITH N-BROMOSUCCINIMIDE
Ajay Kumar,1 Poonam Lohan,2 and Om Prakash1
1Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra,
India
2Department of Chemistry, Kurukshetra University, Kurukshetra, India
GRAPHICAL ABSTRACT
Abstract Bromination of dehydroacetic acid has been carried out with N-bromosuccinimide
under various conditions. The reactions led to selective bromination, thereby offering
efficient synthesis of 3b-bromodehydroacetic acid (3), 3b,5-dibromodehydroacetic acid
(4), 3b,3b-dibromodehydroacetic acid (5), and 3b,3b,5-tribromodehydroacetic acid (6).
Keywords 3-Acetyl-4-hydroxy-6-methyl-2H-pyran-2-one; a-bromo ketones; dehydroace-
tic acid; a,a-dibromoketones; microwave irradiation; N-bromosuccinimide
INTRODUCTION
3-Acetyl-4-hydroxy-6-methyl-2H-pyran-2-one (dehydroacetic acid, DHA, 1) and
its derivatives[1–4] are important precursors for the synthesis of a variety of organic com-
pounds. Investigations in the chemistry and biology of pyran-2-ones have intensified
with the recognition that they are essential pharmacophores in many naturally occurring
and biologically active agents. In view of these observations, efforts are continuously
being made to develop efficient synthetic pathways for the synthesis of various
DHA derivatives. Within this context, studies dealing with bromination of DHA are
significant as the resulting brominated products such as a-bromoketones 3, 4 and a,
a-dibromoketones 5, 6 (Fig. 1) are potential precursors for the synthesis of various
heterocyclic compounds.
We have already reported the synthesis of pyranylthiazoles[5] of potential bio-
logical interest by reaction of 6 with various thioureas=thioamides.
The reported work on bromination[6,7] of DHA makes the use of bromine and
HBr, which have several environmental problems.[8,9] Handling of liquid bromine,
Received January 8, 2011.
Address correspondence to Om Prakash, Institute of Pharmaceutical Sciences, Kurukshetra
University, Kurukshetra 136 119, India. E-mail: dromprakash50@rediffmail.com
2739

2740
A. KUMAR, P. LOHAN, AND O. PRAKASH
Figure 1. Different bromoderivatives of dehydroacetic acid.
because of its hazardous nature, is troublesome. To overcome these problems, alter-
native methods[10,11] avoiding the use of liquid bromine have been developed.
Most recent developments in this area emphasize the advantageous use of N-
bromosuccinimide (NBS)[12–16] over Br2 under suitable conditions, making NBS
the reagent of choice for the following reasons:
1. Ease of handling
2. Selectivity of the reaction in appropriate conditions
3. Yields of the products
4. Environmental friendliness
5. Efficiency of the reaction
As a part of our ongoing program aimed at the development of DHA-based reac-
tions, we now investigate the bromination of DHA using NBS. Consequently, we
report here an efficient and convenient synthesis of bromo derivatives of DHA, namely
3b-bromodehydroacetic acid (3), 3b,5-dibromodehydroacetic acid (4), 3b,3b-dibromo-
dehydroacetic acid (5), and 3b,3b,5-tribromodehydroacetic acid (6).
RESULTS AND DISCUSSION
We started our work by treatment of DHA with NBS under different sets of
conditions. These reactions led to selective bromination of DHA with the formation
of different products depending upon the reaction conditions. The results are dis-
cussed according to individual target molecules.
3b-Bromodehydroacetic Acid (3)
First, DHA was treated with 1 equivalent of NBS in acetonitrile under reflux.
The reaction did not attain the stage of completion even after 12 h. In the course of
our search for efficient methods for bromination,[17] we envisioned that the reaction
could proceed efficiently by using a catalyst such as p-TsOH.[18] Thus, DHA was

BROMINATION OF DEHYDROACETIC ACID
2741
Scheme 1. Synthesis of 3b-bromodehydroacetic acid (3) from dehydroacetic acid (1).
treated with NBS in acetonitrile in the presence of p-TsOH under reflux. The reac-
tion afforded the desired product 3 in 64% yield (Scheme 1).
To study the effect of the nature of protic acid on the reaction involving use
of NBS in acetonitrile, variations of protic acid including trifluoroacetic acid and
sulfuric acid were attempted. The complete results are summarized in Table 1.
It is clear from the results that the use of protic acids such as p-TsOH and
trifluoroacetic acid (TFA) gives satisfactory results, whereas in the case of H2SO4
results are somewhat poorer. Although this method provides a better way for selec-
tive a-bromination,[18–20] there was scope for further improvement of yields.
In view of the encouraging recent reports[21] on the advantages of using
solvent-free reaction conditions (SFRC) in bromination, we attempted the bromination
of DHA under SFRC using conventional heating and microwave irradiation (Scheme 2).
The results of these experiments summarized in Table 2 reveal that the reaction
occurs more efficiently in solvent-free conditions under microwave irradiation.
It is important to mention here that preparation of 3 was previously reported by
Harris et al.[3] using Br2 and HBr in 50% yield. The results of present study are superior
to the reported one in terms of time, yields, and ecofriendly nature of the reagent.
3b,5-Dibromodehydroacetic Acid (4)
Encouraged by these results, we examined the bromination of 5-bromodehy-
droacetic acid using NBS under various conditions (Scheme 3).
The reaction occurred according to our expectation, leading to the regioselec-
tive synthesis of 4. The results summarized in Table 2 again reveal that the
solvent-free reaction conditions using microwave heating give the best yields.
Table 1. Effect of nature of protic acid on a-bromination of dehydroacetic acid
Reaction condition
Time (h)
Yielda (%)
NBS=p-TsOH=CH3CN
NBS=CF3COOH=CH3CN
NBS=H2SO4=CH3CN
9
12
16
64
63
53
aYields of isolated products with regard to NBS.

2742
A. KUMAR, P. LOHAN, AND O. PRAKASH
Scheme 2. Solvent-free synthesis of 3b-bromodehydroacetic acid (3) from dehydroacetic acid (1).
Table 2. Bromination of dehydroacetic acid under various conditions
Reaction conditionsa
Condition (i)
Yieldb (%)
Condition (ii)
Yieldb (%)
Condition (iii)
Yieldb (%)
Substrate
Time
Time
Time
Product
1
2
1
3
4
9 h
64
61
57
69
59
6.30 h
7.35 h
6.05 h
6.35 h
6 h
69
68
64
79
76
5 min
10 min
9 min
89
83
71
88
85
3
4
5
5
6
9.30 h
6.15 h
6 h
5 min
14 min
6.15 h
aCondition (i), NBS=CH3CN=p-TsOH; condition (ii), NBS=p-TsOH=conventional heating; and
condition (iii), NBS=p-TsOH=microwave irradiation.
bYields of isolated products w.r.t NBS.
Scheme 3. Synthesis of 3b,5-dibromodehydroacetic acid (4) from 5-bromodehydroacetic acid (2) under
different conditions.

BROMINATION OF DEHYDROACETIC ACID
2743
Scheme 4. Synthesis of 3b,3b-dibromodehydroacetic acid (5) from 3b-bromodehydroacetic acid (3) under
different conditions.
3b, 3b-Dibromodehydroacetic Acid (5)
Keeping in view the fact that the a,a-dibromo ketones can be used as a superior
alternative to a-bromo ketones[22–24] in the synthesis of various heterocyclic com-
pounds, we attempted the preparation of a,a-dibromo derivative 5 from the bromin-
ation of 3 (Scheme 4). Accordingly 3 was treated with 1.1 equivalents of NBS using
p-TsOH in acetonitrile. The reaction afforded the desired dibromo derivative 5 in
69% yield, together with a trace amount (8%) of 4. Interestingly, solvent-free syn-
thesis proved to be very beneficial in obtaining 5 as pure compound in good yield.
We have also synthesized 5 directly from dehydroacetic acid by treatment with
2.5 equivalent of NBS under various conditions (Scheme 5). The results are summar-
ized in Table 2.
3b,3b,5-Tribromodehydroacetic Acid (6)
In the light of successful results on the preparation of 3–5, we finally carried out
the synthesis of 6. Tribromoderivative of DHA was prepared from 4 by treatment with
NBS under different conditions (Scheme 6). All results are summarized in Table 2.
Scheme 5. Synthesis of 3b,3b-dibromodehydroacetic acid (5) from dehydroacetic acid (1) under different
conditions.

2744
A. KUMAR, P. LOHAN, AND O. PRAKASH
Scheme 6. Synthesis of 3b,3b,5-tribromodehydroacetic acid (6) from 3b,5-dibromodehydroacetic acid (4)
under different conditions.
It is worthwhile mentioning that the synthesis of a,a-dibromo ketone 6 in 68%
yield has been previously reported by the action of bromine on DHA, though we
have developed an alternate method using an environmentally friendly reagent
(NBS) for bromination.
CONCLUSION
These results clearly indicate that NBS-mediated bromination of DHA offers a far
better alternative to the existing methods involving Br2=HBr. Further, the by-product
succinimide can be readily recovered and recycled, thus making the procedure more
environmentally acceptable. In particular, the solvent-free approach is remarkable in
terms of simplicity, selectivity, short reaction times, and good yields of products.
EXPERIMENTAL
All reagents were purchased from commercial sources and were used without
purification. Melting points were taken on slides in an electrical apparatus (Labindia
visual melting-range apparatus) and are uncorrected. Infrared (IR) spectra were
recorded on a Perkin-Elmer 1800 Fourier transform (FT)–IR spectrophotometer.
1H NMR spectra was recorded on a Bruker 300-MHz instrument using tetramethyl-
silane (TMS) as internal standard. Microwave-assisted reactions were carried out in
a domestic microwave oven (Power Solo 17 D, 1200 W, 2450 MHz).
3b-Bromodehydroacetic Acid (3-Bromoacetyl-4-hydroxy-6-methyl-
2H-pyran-2-one, 3)
NBS was slowly added (1.96 g, 11.0 mmol) to a solution of 1 (1.68 g, 10.0 mmol)
and p-toluenesulphonic acid monohydrate (2.85 g, 15.0 mmol) in acetonitrile (20 ml)
in small amounts to avoid dibromination. The mixture was stirred for 9 h under
reflux. Then the solvent was reduced by distillation to half and cooled down to room
temperature, and the resulting solid was dissolved in dichloromethane, washed with
water, and recrystallized using ethanol to give 1.58 g (64%) of bromopyrone 3: mp

BROMINATION OF DEHYDROACETIC ACID
2745
1
118–120 ꢀC (lit.[6] 118–119 ꢀC); IR (vmax, cmÀ1, KBr): 3335, 1732, 1641; H NMR
(CDCl3, d): 2.33 (s, 3H), 4.71 (s, 2H), 6.03 (s, 1H), 15.6 (s, 1H).
3b,5-Dibromodehydroacetic Acid (5-Bromo-3-bromoacetyl-
4-hydroxy-6-methyl-2H-pyran-2-one, 4)
NBS was slowly added (0.98 g, 5.5 mmol) to a solution containing 1.23 g
(5.0 mmol) of 2 and 1.43 g (7.5 mmol) of p-toluenesulphonic acid monohydrate in
acetonitrile (20 ml). In small amounts to avoid dibromination. The mixture was stir-
red for 9.30 h under reflux. Then, the reaction mixture was reduced and cooled down
to room temperature, and the residue was dissolved in dichloromethane, washed
with water, dried, and recrystallized using ethanol to gave 0.98 g (61%) of 4: mp
1
128–130 ꢀC (lit.[6] 129–131 ꢀC); IR (vmax, cmÀ1, KBr): 3405, 1728, 1620; H NMR
(CDCl3, d): 2.54 (s, 3H), 4.72 (s, 2H).
3b,3b-Dibromodehydroacetic Acid (3,3-Dibromoacetyl-4-hydroxy-
6-methyl-2H-pyran-2-one, 5)
NBS was slowly added (0.98 g, 5.5 mmol) to a solution containing (1.23 g,
5.0 mmol) of 3 and 1.43 g (7.5 mmol) of p-toluenesulphonic acid monohydrate in
acetonitrile (20 ml). The mixture was stirred for 6 h under reflux. Then the reaction
mixture was reduced and cooled down to room temperature, and the residue was
dissolved in dichloromethane, washed with water, dried using anhydrous sodium sul-
fate, and recrystallized to afford dibromoderivative (0.98 g, 59%) of 5: mp 84–86 ꢀC
(lit.[6] 85–86 ꢀC); IR (vmax, cmÀ1, KBr): 3400, 1730, 1630, 1570; 1H NMR (CDCl3, d):
2.4 (s, 3H), 7.4 (s, 1H), 6.04 (s, 1H).
3b,3b,5-Tribromodehydroacetic Acid (5-Bromo-3,3-dibromoacetyl-
4-hydroxy-6-methyl-2H-pyran-2-one, 6)
NBS was slowly added (1.02 g, 5.7 mmol) to a solution containing 1.68 g
(5.2 mmol) of 4 and 1.48 g (7.8 mmol) of p-toluenesulfonic acid monohydrate in acet-
onitrile (20 ml). of NBS. The mixture was stirred for 6.15 h under reflux. After that
the reaction mixture was reduced and cooled down to room temperature, and the
residue was dissolved in dichloromethane, washed with water, dried using anhydrous
sodium sulfate, and recrystallized using ethanol to gave 1.45 g (69%) of 6: mp
102–103 ꢀC (lit.[7] 102–103 ꢀC); IR (vmax, cmÀ1, KBr): 3406, 1731; 1H NMR (CDCl3,
d): 2.56 (s, 3H), 7.4 (s, 1H), 16.3 (s, 1H).
Conventionally Heated Bromination Reaction
The substrate (1.00 mmol) (1, 2, 3, or 4), NBS (1.1 mmol), and p-TsOH
(1.5 mmol) were taken and heated under a reflux condenser at 80–90 ꢀC for the
appropriate time as given in Table 2 for the preparation of various bromoderiva-
tives. Then reaction mixtures were cooled to room temperature and poured into
water to remove succinimide. The solid crude products were collected by decantation
or filteration and dried to gave bromopyrones.

2746
A. KUMAR, P. LOHAN, AND O. PRAKASH
Microwave-Accelerated Bromination Reaction
The substrate (1.00 mmol) (1, 2, 3, or 4), NBS (1.1 mmol), and p-TsOH
(1.5 mmol) were taken, and reaction vessels were submitted to microwave irradiation
for the appropriate time as shown in Table 2. Then, reaction mixtures were cooled
rapidly, washed with water to remove succinimide, and recrystallized using ethanol
to gave pure bromoderivatives of DHA.
ACKNOWLEDGMENT
We are thankful to the Council of Scientific and Industrial Research, New
Delhi, for the award of a junior research fellowship to Poonam Lohan to carry
out this work.
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