A mild and regioselective method for α-bromination of β-keto esters and 1,3-diketones using bromodimethylsulfonium bromide (BDMS)

Article abstract of DOI:10.1021/jo061501r

Bromodimethylsulfonium bromide has been found to be an effective and regioselective reagent for α-monobromination of β-keto esters and 1,3-diketones. A wide variety of β-keto esters and 1,3-diketones undergo chemoselective α-monobromination with excellent yields at 0-5 °C or room temperature. The notable advantages of this protocol are no need of chromatographic separation, use of less hazardous reagent than molecular bromine, and no added base, Lewis acid, or other catalyst.

Full text of DOI:10.1021/jo061501r

A Mild and Regioselective Method for
r-Bromination of â-Keto Esters and
,3-Diketones Using Bromodimethylsulfonium
Bromide (BDMS)
methods in the literature provide good yields, most of them
suffer from limitations; for example, molecular bromine is
hazardous and difficult to handle, the use of Lewis acid as an
additive or strong bases may be required, and sometimes the
reaction needs to be performed under dry and inert atmospheric
conditions. From the literature it is apparent that the chemose-
lective R-monobromination of unsubstituted â-ketoesters or 1,3-
diketones is a very challenging task since some of the
monobrominated products are reported to be unstable and to
undergo disproportionations to dibromo and debrominated
1
Abu T. Khan,* Md Ashif Ali, Papori Goswami, and
Lokman H. Choudhury
Department of Chemistry, Indian Institute of Technology
Guwahati, Guwahati 781 039, India
1
1
products. In continuation of our effort in the field of new
synthetic methodologies using bromodimethylsulfonium bro-
atk@iitg.ernet.in
1
2
mide in various organic transformations, we were in search
of a new and improved synthetic protocol for chemo- and
regioselective R-monobromination of â-keto esters and 1,3-
diketones that could be applied to a wide range of substituted
and unsubstituted â-keto esters and 1,3-diketones. So far, BDMS
has been utilized for the transformations of alcohols to the
ReceiVed July 19, 2006
1
3
14
corresponding bromides, oxidation of thiols to disulfides,
1
5
deprotection of dithioacetals, and preparation of R-bro-
1
6
moenones from the corresponding enones. Recently, we have
demonstrated that the peroxo vanadium mediated oxidation of
bromide ion to bromonium ion can be utilized for selective
R-monobromination of â-keto esters and 1,3-diketones.17 In-
terestingly, we have noted by our earlier method that some of
the substrates did not provide monobrominated product exclu-
sively. However, by employing bromodimethylsulfonium bro-
mide, it is possible to prepare selectively monobrominated
products. In addition, it offers a wealth of advantages in
comparison with the earlier reported methods, e.g., the reagent
BDMS is readily accessible, can be considered a convenient
storage of molecular bromine, is less hazardous and easy to
handle, and facilitates maintaining the stoichiometric ratio while
carrying out the reactions. In this note, we report that BDMS is
a convenient and valuable reagent for highly selective R-bro-
mination of â-keto esters and 1,3-diketones at 0-5 °C or room
temperature under mild reaction conditions without using any
base or Lewis acid or any other additive, as shown in Scheme
1.
Bromodimethylsulfonium bromide has been found to be an
effective and regioselective reagent for R-monobromination
of â-keto esters and 1,3-diketones. A wide variety of â-keto
esters and 1,3-diketones undergo chemoselective R-mono-
bromination with excellent yields at 0-5 °C or room
temperature. The notable advantages of this protocol are no
need of chromatographic separation, use of less hazardous
reagent than molecular bromine, and no added base, Lewis
acid, or other catalyst.
The regioselective R-bromination of â-keto esters and 1,3-
1
diketones is a useful transformation in organic synthesis. These
brominated products serve as valuable building blocks for the
2
synthesis of both natural and non-natural products. Over the
years, several methods have been developed for the bromination
1
of 1,3-dicarbonyl compounds. Conventionally, molecular bro-
3
2a
2d
4
For the present study, the catalyst bromodimethylsulfonium
bromide (BDMS) was prepared by following the literature
mine, bromine/NaH, NBS/Et3N, and NBS/NaH are used
to access these compounds. In addition, other reagents such as
1
5
2c
procedure. In the preliminary experiment, when methyl
CuBr2 with [hydroxy(tosyloxy)iodo]benzene or NBS/Mg-
ClO4)2 or NaOBr in acetone/acetic acid or NBS in various
combinations such as silica-supported NaHSO4 or Amberlyst-
5 or sulfonic acid functionalized silica or in ionic liquids
5
6
(
(
8) Meshram, H. M.; Reddy, P. N.; Sadashiv, K.; Yadav, J. S.
7
Tetrahedron Lett. 2005, 46, 623.
(9) Das, B.; Vankateswarlu, K.; Holla, H.; Krishnaiah, M. J. Mol. Catal.
A: Chem. 2006, 253, 107.
8
9
10
1
are also utilized for similar transformation. Though several
(10) Meshram, H. M.; Reddy, P. N.; Vishnu, K.; Sadashiv, K.; Yadav,
J. S. Tetrahedron Lett. 2006, 47, 991.
(
1) Larock, R. C. ComprehensiVe Organic Transformations, 2nd ed; VCH
Publishers Inc.: New York, 1999; pp 717-718.
2) (a) Stotter, P. L.; Hill. K. A. Tetrahedron Lett. 1972, 13, 4067. (b)
Yoshida, J.; Yano, S.; Ozawa, T.; Kawabata, N. Tetrahedron Lett. 1984,
2
7
(11) (a) Hoffman, R. V.; Weiner, W. S.; Maslouh, N. J. Org. Chem.
2001, 66, 5790. (b) Honda, Y.; Katayama, S.; Kojima, M.; Suzuki, T.; Izawa,
K. Org. Lett. 2002, 4, 447.
(12) (a) Khan, A. T.; Islam, S.; Majee, A.; Chattopadhyay, T.; Ghosh,
S. J. Mol. Catal. A: Chem. 2005, 239, 158. (b) Khan, A. T.; Sahu, P. R.;
Majee, A. J. Mol. Catal. A: Chem. 2005, 226, 207. (c) Khan, A. T.; Mondal,
E.; Ghosh, S.; Islam, S. Eur. J. Org. Chem. 2004, 2002. (d) Khan, A. T.;
Mondal, E.; Borah, B. M.; Ghosh, S. Eur. J. Org. Chem. 2003, 4113.
(13) Furukawa, N.; Inoue, T.; Aida, T.; Oae, S. J. Chem. Soc., Chem.
Commun. 1973, 212.
(14) Olah, G. A.; Arvanaghi, M.; Vankar, Y. D. Synthesis 1979, 721.
(15) Olah, G. A.; Vankar, Y. D.; Arvanaghi, M.; Surya Prakash, G. K.
Synthesis 1979, 720.
(16) Chow, Y. L.; Bakker, B. H. Can. J. Chem. 1982, 60, 2268.
(17) Khan, A. T.; Goswami, P.; Choudhury, L. H. Tetrahedron Lett. 2006,
47, 2751.
(
5, 2817. (c) Coats, S. J.; Wasserman, H. H. Tetrahedron Lett. 1995, 36,
735. (d) Bateson, J. H.; Quinn, A. M.; Southgate, R. J. Chem. Soc., Chem.
Commun. 1986, 1151.
3) Hakam, K.; Thielmann, M.; Thielmann, T.; Winterfeldt, E. Tetra-
hedron 1987, 43, 2035.
4) Curran, D. P.; Bosch, E.; Kaplan, J.; Newcomb, M. J. Org. Chem.
989, 54, 1826.
(
(
1
2
(
5) Yang, D.; Yan, Y.; Lui, B. J. Org. Chem. 2002, 67, 7429.
(6) Meketa, M. L.; Mahajan, Y. R.; Weinreb, S. M. Tetrahedron Lett.
005, 46, 4749.
7) Das, B.; Venkateswarlu, K.; Mahender, G.; Mahender, I. Tetrahedron
Lett. 2005, 46, 3041.
(
1
0.1021/jo061501r CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/11/2006
J. Org. Chem. 2006, 71, 8961-8963
8961

TABLE 1. r-Bromination of â-Keto Esters and 1,3-Diketonesa
SCHEME 1. Selective r-Bromination of â-Keto Esters and
,3-Diketones
1
acetoacetate (1 mmol) was treated with bromodimethylsulfonium
bromide (1.25 mmol) in dichloromethane (5 mL) at 0-5 °C, it
provided exclusively monobrominated product within 20 min
in 85% yield. The product 1b was characterized by recording
1
13
H and C NMR spectra and elemental analysis. Interestingly,
we did not observe any detectable amount of dibrominated
product under the experimental conditions while recording the
1
H NMR spectrum of the crude product. Encouraged by this
result, we tried to apply this protocol to a wide range of â-keto
esters. Similarly, other unsubstituted â-keto esters (Table 1,
entries 2a and 3a) underwent R-bromination smoothly under
similar conditions and afforded exclusively monobrominated
product in excellent yields. For further investigation, a wide
variety of â-keto esters (Table 1, entries 4a-8a and 10a) were
prepared by transesterification of methyl acetoacetate with their
corresponding alcohols using a silica-supported perchloric acid
18
method. By following the identical reaction procedure, various
substrates 4a-9a were converted to the desired R-monobro-
minated products in very good yields. Next, the di-keto ester
of octanediol (10a) was treated with 2.5 equiv of BDMS, and
the desired monobrominated product 10b was found in very
good yield. The notable advantages of this protocol over the
other existing methods are that the conversion takes place within
a very short time without using any catalyst and there is no
need of chromatographic separation, as it gives full conversion
of the starting material with a single product. NMR spectra of
all the products were recorded from crude product just after
aqueous workup without any further purifications and showed
high purity without detectable byproducts. To explore further,
monosubstituted â-keto esters (entries 11a-13a) were prepared
by alkylation of â-keto esters using K2CO3 as base by following
a standard procedure. Subsequently, the substrates 11a-13a
were treated with BDMS following the same experimental
procedure and provided the monobrominated products 11b-
1
3b, respectively, in good yields at room temperature. As there
is no probability for dibromination, we performed the reactions
at room temperature instead of ice-bath temperature. Similarly,
a cyclic â-keto ester (entry 14a) underwent R-bromination
smoothly in good yield at room temperature. Likewise, various
1
,3-diketones (Table 1, entries 15a-17a) provided the desired
R-monobrominated products 15b-17b exclusively with very
good yields under the given experimental conditions.
Interestingly, dimedone (entry 18a) provided exclusive mono-
brominated product at room temperature, which is sometimes
9
difficult to achieve by some of the reported methods. Surpris-
ingly, we could not find the proton attached with the R-bromi-
1
nated carbon atom of compound 18b in the H NMR spectrum.
We observed only two signals at 1.12 (s) and 2.48 (s),
respectively. Also, in the IR spectrum, we did not observe any
carbonyl peak of this product. Therefore, to further confirm the
structure of compound 18b, whether the product is mono- or
dibrominated, the product was recrystallized from ethyl acetate/
a
Reaction conditions: â-keto ester/1,3-diketone (1 mmol), BDMS (0.278
b
g, 1.25 mmol), 0 °C to rt, 20-30 min. Reactions were carried out at 0
°C. c Reactions were performed at room temperature. Bromodimethyl
d
e
sulfonium bromide (2.5 equiv) was used. Reaction time was 30 min.
hexane (7:3) and a single-crystal XRD was recorded. Interest-
ingly, we found that in solid state it exists in enol form as shown
(
18) Khan, A. T.; Goswami, P.; Kalpana, K.; Choudhury, L. H.
Unpublished work.
8
962 J. Org. Chem., Vol. 71, No. 23, 2006

SCHEME 3. Probable Mechanism for Selective
Monobromination
no need of any base or Lewis acid as an additive, which is
invariably required by NBS methods. Furthermore, this method
is also expected to have valuable application in organic synthesis
because of the low cost, easy accessibility, and less hazardous
nature of the reagent.
Experimental Section
Preparation of Bromodimethylsulfonium Bromide (BDMS).15
Dimethyl sulfide (1.83 mL, 25 mmol) was taken in 5 mL of dry
dichloromethane into a 150 mL standard joint conical flask. Then,
1.3 mL of bromine (25 mmol) was dissolved in 5 mL of dry
dichloromethane and added slowly into the above solution at ice-
bath temperature over a period of 5 min. During the addition, light
orange crystals of bromodimethylsulfonium bromide begin to
separate out. After the addition of bromine was completed, the
crystals of bromodimethylsulfonium bromide were collected by
filtration. The solid material was then washed with dry hexane and
dried under vacuum. The crystalline product was obtained as 4.3 g
in 77% yield, mp 80 °C.
FIGURE 1. ORTEP plot of R-monobromo dimedone with atom
numbering scheme.
SCHEME 2. Rapid Keto-Enol Tautomerization in Solution
General Procedure for R-Bromination of â-Keto Esters and
,3-Diketones. Bromodimethylsulfonium bromide (BDMS) (1.25
1
mmol, 0.278 g) was added to a stirred solution of â-keto ester or
,3 diketone (1 mmol) in CH Cl (5 mL) at 0-5 °C or room
temperature. After 20 min, the reaction mixture was washed with
water (10 mL × 2) and extracted with CH Cl (10 mL × 2). The
4
organic layers were combined and dried over anhydrous Na SO ,
and solvents were removed by evaporation in a rotary evaporator
to get the crude product. All products were characterized without
any further purification.
1
2
2
in the ORTEP diagram of Figure 1, which shows intermolecular
hydrogen bonding of O-H of enol and ketonic CO of the other
unit. We believe that in solution state it undergoes rapid keto-
enol tautomerization as shown in Scheme 2, for which we do
not observe the proton signal for the R-hydrogen associated with
the brominated carbon.
2
2
2
Next, to exemplify further the applicability of this protocol,
the substrate 19a was treated under the experimental conditions.
Interestingly, the allylic double bond survives under the given
conditions and provided the desired product 19b in good yields.
A probable mechanism is depicted in Scheme 3. We believe
that bromodimethylsulfonium bromide facilitates the enol
formation of â-keto esters or 1,3-diketones. In addition, bro-
modimethylsulfonium ion may also bind with the enol form of
the monobrominated product, which provides extra stability of
the monobrominated product and as a result makes the process
sluggish for further bromination or disproportionation.
In conclusion, we have devised a simple and efficient
synthetic protocol for highly selective R-monobromination of
â-keto esters and 1,3-diketones using the versatile reagent
bromodimethylsulfonium bromide. The notable advantages of
this protocol are mild, clean, and simple reaction conditions;
very good yields; no need of chromatographic separations; and
Acknowledgment. P.G and L.H.C. are thankful to Council
of Scientific and Industrial Research, New Delhi for their
research fellowships. We also acknowledge Department of
Science and Technology, New Delhi for providing single XRD
facility under FIST program (sanction no. SR/FST/CSII-007/
2
003). The authors are also thankful to the Director, IIT
Guwahati for the general facilities to carry out the research work
and are grateful to the reviewers for their valuable comments
and suggestions.
Supporting Information Available: Experimental details and
1
13
analytical data of all products and H and C NMR spectra of
unknown compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO061501R
J. Org. Chem, Vol. 71, No. 23, 2006 8963