Tetrahedron Letters
Electrophilic aryl-halogenation using N-halosuccinimides under
ball-milling
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Anima Bose, Prasenjit Mal
School of Chemical Sciences, National Institute of Science Education and Research (NISER) Bhubaneswar, Institute of Physics Campus, PO Sainik School, Bhubaneswar, Odisha 751
005, India
a r t i c l e i n f o
a b s t r a c t
Article history:
We report here a methodology of chemo- and regio-selective aryl bromination and iodination using
respective N-halosuccinimides at room temperature in the absence of any solvents, catalyst/additives
under ball-milling condition. However, for chlorination ceric ammonium nitrate was used as additive.
The coupled product succinimide, produced from the reactions, was recycled via regeneration of NBS.
This methodology works with the electron-donor substituted or unsubstituted arenes.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 9 January 2014
Revised 17 February 2014
Accepted 18 February 2014
Available online 25 February 2014
Keywords:
Ball-milling
Mechanochemistry
Aryl halogenation
N-halosuccinimide
Solvent free
It is essential to minimize the usage of chemicals, solvents and
catalysts in routine organic synthesis to do chemical reactions in
greener way.1,2 Aryl halides are well known synthetic intermedi-
ates towards the synthesis of natural or pharmaceutical products.3
The aryl halogenation methodologies are well known over a cen-
tury but still need modifications because of high demand for better
methodologies. For example, bromination reactions using elemen-
tal bromine may lead to unwanted side reactions at harsh condi-
tions4 and chlorination reagents are generally non-eco-friendly.
We did focus on a few literature known halogenation procedures
relevant to our studies (a) brominations using NBS5 (N-bromosuc-
cinimide): NBS–acetonitrile,6 NBS–H2SO4–TFA,7 NBS–BF3–H2O,8
NBS–Al2O3 (solvent free condition9 and Vilsmeier–Haack
bromination10 (b) for chlorinations: NCS (N-chlorosuccinimide)–
in the absence of any catalyst or additives. However, chlorination
was done using NCS–CAN (ceric ammonium nitrate) combination.
Interestingly, the coupled product succinimide, obtained from the
reaction, was reprocessed for preparation of NBS. It has been found
that this newly generated NBS works efficiently without losing its
activity. This is an unprecedented example in the literature where
NBS and NIS work efficiently in the absence of any additive/
catalyst.
The results of aryl brominations are presented in Figure 1. Bro-
minated products were obtained in very good to excellent yield for
the derivatives of anilines, anisoles, benzaldehydes, nitrobenzene,
alkyl benzenes etc. Taking a few examples into consideration, we
are now examining the efficiency of our methodology. As shown
in Figure 1, 2h was prepared in 2 h using only NBS under ball-mill-
ing condition compared to a literature reported procedure in which
the bromination was done for 18 h using NBS–TFA–H2SO4.21 We
have successfully done the bromination of alkyl benzenes (2c–2f,
Fig. 1) in the absence of hazardous molecular bromine.4 The ring
brominations of anisole derivatives are generally performed in
toxic acetonitrile solvent and NBS.6 However, the synthesis of 2m
was done at 45 min at ambient temperature under ball-milling
rather than 24 h at reflux condition (Table 1).6 In a similar manner
we have made a few comparisons with literature reported data and
our method (ball milling). These data are shown in Table 1.
The reactions were done under ball-milling condition (fre-
quency 21 Hz), in solid state and at room temperature. The pro-
gress of the reactions was monitored by either TLC (thin layer
acetonitrile,11 NCS–CuCl12 and NCS–BF3–H2O8 (c) iodinations: NIS
14
(N-iodosuccinimide)–TFA,13 NIS–In(OTf)3
NO2–I2 etc.
NIS–BF3–H2O8 and
15
We report a synthetic methodology for electrophilic aryl halo-
genations under ball-milling16–18 conditions and solvent-free con-
ditions at room temperature. To the best of our knowledge, only
one example of aryl-bromination under ball-milling condition
using oxone–NaBr is known in literature.19,20
Herein, we have demonstrated the bromination and iodination
reactions using NBS and NIS, respectively. This methodology works
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0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.