Atom-economical brominations with tribromide complexes in the presence of oxidants

Article abstract of DOI:10.1016/j.tetlet.2019.03.011

Bromination is an important transformation in organic synthesis, and novel efficient bromination techniques are still required. Herein, we demonstrate atom-economical brominations using (DMI)₂HBr₃, a novel tribromide complex, with oxidants such as DMSO and Oxone. Using this system, olefinic and aromatic brominations, as well as selective α-monobrominations of ketones proceeded well to afford the desired bromides in good yields. Importantly, in these reactions all of the bromine atoms in this complex are used to brominate.

Full text of DOI:10.1016/j.tetlet.2019.03.011

Accepted Manuscript
Atom-economical brominations with tribromide complexes in the presence of
oxidants
Kotaro Yubata, Hiroshi Matsubara
PII:
S0040-4039(19)30219-9
https://doi.org/10.1016/j.tetlet.2019.03.011
TETL 50652
DOI:
Reference:
Tetrahedron Letters
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25 January 2019
4 March 2019
5 March 2019
Please cite this article as: Yubata, K., Matsubara, H., Atom-economical brominations with tribromide complexes
in the presence of oxidants, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.03.011
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Atom-economical brominations with
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Kotaro Yubata and Hiroshi Matsubara*

1
Tetrahedron Letters
Atom-economical brominations with tribromide complexes in the presence of
oxidants
Kotaro Yubata and Hiroshi Matsubara*
Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Bromination is an important transformation in organic synthesis, and novel efficient
bromination techniques are still required. Herein, we demonstrate atom-economical
brominations using (DMI)2HBr3, a novel tribromide complex, with oxidants such as DMSO
and Oxone. Using this system, olefinic and aromatic brominations, as well as selective -
monobrominations of ketones proceeded well to afford the desired bromides in good yields.
Importantly, in these reactions all of the bromine atoms in this complex are used to brominate.
Available online
Keywords:
DMI
Oxidants
Bromination
Tribromide complex
2009 Elsevier Ltd. All rights reserved.
bromine, we focused on the use of the HBr ‘discarded’ from
complex 2. It is known that Br2 is generated by the oxidation of
bromide ion. For example, Karki et al. reported the preparation
of bromodimethylsulfonium bromide (BDMS, 3) from HBr and
1. Introduction
Bromination is a fundamental process in organic chemistry
and the products of bromination reactions, namely
dimethyl sulfoxide (DMSO) [6], applied 3 in many bromination
reactions, and concluded that compound 3 is a useful brominating
reagent. During the preparation of 3, HBr is oxidised with
DMSO. With this in mind, we applied the concept used to
prepare 3 to the generation of Br2 from the HBr in DITB 2. In
this study, we used complex 2 for several reactions, including
olefinic and aromatic brominations, and -bromination of
carbonyl compounds in the presence of an oxidant. On the other
hand, aromatic brominations and the -brominations of carbonyl
compounds generate HBr as the byproduct, which we also used
as a source of Br2 in this system.
organobromides, are useful as building blocks in organic
synthesis as well as functional materials, such as fire retardants.
Traditionally, molecular bromine (Br2) has been used in this
chemistry [1]; however, Br2 is troublesome to handle due to its
intrinsic toxicity and volatility. In order to circumvent this
problem, various brominating reagents, such as N-
bromosuccinimide (1a) [2], dioxane dibromide (1b) [3], and
tetrabutylammonium tribromide (TBATB, 1c) [4], have been
reported. Recently, a novel brominating reagent, namely bis(1,3-
dimethylimidazolidinone) hydrotribromide (DITB, 2), was
developed in our research group [5]. DITB (2, (DMI)2HBr3) is a
complex between two 1,3-dimethylimidazolidinone (DMI)
molecules and HBr3. The brominating ability of complex 2 was
examined in several organic reactions. This complex provided
reaction products in yields that were almost the same or superior
to those using other bromine alternatives; hence 2 can be used in
many bromination reactions as an alternative to Br2.
2. Results and discussion
2.1. Bromination of alkenes
We began our investigation by brominating aliphatic and
aromatic alkenes with complex 2 in the presence of DMSO.
Ideally, this complex should be able to brominate 1.5 equivalents
of an alkene since 2 contains three bromine atoms; hence, we
brominated styrene (4a, 1.5 mmol, 1.5 equiv.) with 2 (1.10
mmol) in CH2Cl2 (2 mL) in the presence of DMSO (0.55 mmol,
0.5 equiv.) at 25 °C for 1 h, to afford the corresponding
dibrominated product, 1-phenyl-1,2-dibromoethane (5a), in 93%
yield. This result demonstrates that all of the bromine atoms in
complex 2 were used in the bromination chemistry. The yield of
5a decreased to 60% when the reaction was carried out in the
absence of DMSO, which demonstrates that DITB alone is
unable to brominate more than two equivalents of the substrate.
Styrene derivatives 4b and 4c were brominated to afford the
Unfortunately, complex 2 has a fundamental drawback for
practical use. As is evident from its molecular formula, complex
2 contains HBr3, from which Br2 is used to brominate, while HBr
is always discarded. In order to improve atom economy of

2
Tetrahedron Letters
corresponding dibromides 5b and 5c in good yields. Indene
Table 2
(4d) was transformed to the desired product 5d in 83% yield
without any side products, while aliphatic alkenes 4e-4g
furnished the corresponding dibromides 5e-5g in excellent yields.
Optimization of reaction conditions for bromination of 6a
with 2.
Table 1
Bromination of alkenesa with DITB 2/DMSO.
Amount
Entry of 6a
Yield of
Solvent
Oxidant /mmol
7a / %a
/mmol
1
2
3
4
5
6
7
8
1.0
2.0
2.0
2.0
3.0
3.0
3.0
3.0
AcOH
AcOH
AcOH
CH3CN
AcOH
CH3CN
AcOH
AcOH
--
93b
DMSO/1.1
Oxone/1.1
Oxone/1.1
Oxone/1.1
Oxone/1.1
H2O2aq/1.1
NaClO·5H2O/1.1
52
53(31)c
52(25)c
76
5a, 93% (60%)b
5d, 83%
5b, 85%
5c, 89%
92
5e, 95%
5f, 94%
5g, 94%
62
aIsolated yield. bWithout DMSO.
35
aDetermined by NMR. bIsolated yield. cYield of dibromide 7a’.
2.2. Aromatic bromination
Whereas the aromatic bromination of N,N-dimethylaniline
(6a) with 2/oxone was carried out successfully, anisole
derivatives 6b-6d afforded the corresponding bromides in
moderate yields (entries 2, 4, 6). It is well known that 1,1,1,3,3,3-
hexafluoro-2-propanol (HFIP) [7] facilitates many reactions
including Friedel–Crafts acylations [8], Baeyer–Villiger
oxidations [9], and epoxidations [9a][10]. HFIP also promotes
the hydrochlorination of alkynes using HCl [11]. Hence, we
added HFIP to the reaction mixture with extension of reaction
time to 24 h; the mixed solvent (3:1 acetonitrile/HFIP) [12]
effectively promoted the aromatic bromination, with the yields of
bromides 7b, 7c, and 7d improved to 81, 85, and 80%,
respectively (entries 3, 5, 7). Using HFIP as the co-solvent,
anisoles 6e and 6f were brominated in 85 and 72% yields,
respectively (entries 8 and 9); however, pyrrole derivatives 6g-6h
did not afford the desired products, rather the starting materials
were observed to decompose.
We next focused on aromatic brominations with DITB in the
presence of an oxidant. Since HBr is generated as the by-product
in this reaction, complex 2 can ideally brominate three
equivalents of an aromatic compound. Using N,N-
dimethylaniline (6a) as the substrate, we began to optimise the
reaction conditions for bromination, the results of which are
listed in Table 2. DITB has been reported to brominate one molar
equivalent of 6a in 93% yield (entry 1) [5]. However, the use of
DMSO as the oxidant did not result in an increased yield of
brominated product 7a (52%, entry 2). Changing the oxidant to
Oxone (2KHSO5•KHSO4•K2SO4) afforded a similar yield (53%)
of 7a, together with 31% of the dibrominated product 7a’ (entry
3), while the use of acetonitrile as the solvent resulted in a similar
result to that obtained in AcOH: 7a and 7a’ were obtained in
yields of 52% and 25% yields (entry 4). Fortunately, increasing
the amount of 6a to three equivalents relative to oxone led to the
formation of the desired product 7a in 76 and 92% yields without
by-product, 7a’ (entries 5 and 6). These results indicate that
acetonitrile is a better solvent than acetic acid for this
Table 3
Aromatic brominationa with DITB 2/oxone
bromination chemistry. Oxidants other than oxone gave lower
yields of the product (entries 7 and 8). Based on these results, the
optimal conditions were established to involve substrate (3.0
mmol), 2 (1.1 mmol), and oxone (1.1 mmol) in acetonitrile (6
mL) at 50 °C for 6 h (entry 6). The scope of this protocol was
examined under these conditions, the results of which are
summarised in Table 3.
Entry Prodcut
1
Solvent
CH3CN
Yield / %
92(87)b
7a
7b
2
CH3CN
48
81
CH3CN/HFIP
= 3/1
3c

3
dodecanone (8g) bearing two -carbons provided monobromide
9g, in which the terminal methyl group was brominated, in 51%
yield.
4
CH3CN
63
CH3CN/HFIP
= 3/1
5c
6
85(81)b
40
7c
Table 4
-Bromination of ketonesa using DITB 2/oxone
CH3CN
CH3CN/HFIP
= 3/1
7c
80(55)b,d
7d
CH3CN/HFIP
= 3/1
8c
9c
85(69)b,d
7e
CH3CN/HFIP
= 3/1
72
7f
9a, 84%
9d, 83%
9b, 90%
9c, 89%
CH3CN/HFIP
= 3/1
10c
NDe
7g
7h
9g, 51%b
9f, 71%
9e, 76%
CH3CN/HFIP
= 3/1
11c
NDe
aIsolated yield. bDetermined by NMR.
aDetermined by NMR. bIsolated yield. cReaction time 24 h. dSee
Reference and Note [13]. eNot detected by GCMS.
2.4. Bromination using other tribromide complexes in the
presence of oxidants
Finally, we brominated 1-dodecene (4e) and N,N-
dimethylaniline (6a), and acetophenone (8a), with other
tribromide complexes, namely bis(N-
methylpyrrolidone) hydrotribromide
(MPHT, 10) [14] and TBATB 1c in the
presence of oxidants under the optimised
conditions, the results of which are
2.3. Selective monobromination of ketones
We also examined the -brominations of ketones using
DITB/oxidant. In a similar manner to an aromatic system, the -
brominations of ketones also generates HBr; consequently, we
attempted to reuse this HBr as a bromine source. In addition, we
also tried to monobrominate at the -positions of ketones in a
manner that avoided dibromination. Significant amounts of
dibromides are usually formed during -bromination reactions
due to the high reactivities of the generated monobromides.
Nevertheless, we suppressed the formation of the dibromide
using methanol (MeOH) as the solvent; the formation of the
acetal during the reaction is the key to achieving this outcome.
As shown in Table S1 in the Supplementary Material, we
selectively monobrominated the -positions of carbonyl
compounds using HBr/DMSO in MeOH. We then applied these
reaction conditions to -brominate ketones with DITB/oxidant.
Oxone was employed as the oxidant since DMSO was a less-
reactive oxidant in this reaction, as shown in Table S2. Based on
these results, the optimal conditions were established to be: (i)
substrate (3.0 mmol), DITB (1.1 mmol) in MeOH (4.5 mL) at 0
°C for 2 h, (ii) addition of oxone (1.1 mmol) and HFIP (1.5 mL)
at 15 °C followed by stirring at the temperature for 20 h, and (iii)
addition of water (1.0 mL) at 25 °C followed by stirring at the
temperature for 1 h. The substrate scope of this reaction is shown
in Table 4. Acetophenones bearing electron-donating substituents
were transformed into the desired monobromides in yields in
excess of 80% (9a-9d), while 4-chloroacetophenone (8e)
afforded the corresponding product in 76% yield, together with
recovered substrate (9%). Unfortunately, acetophenones bearing
strong electron-withdrawing groups, such as trifluoromethyl or
nitro, did not afford the desired monobromide using this
technique. Pinacolone (8f), an aliphatic ketone, was also
examined, giving the desired product in 71% yield, while 2-
summarised in Table 5.
Table 5
Bromination using tribromide complexes in the presence of
oxidants.
Isolated yield / %
Substrate
Product
DITB MPHT TBATB
2
10
1c
95
93
77
4e
5e
87
84
85
83
80
4
6a
7a
8a
9a
Complex 10 was also an effective brominating agent and
afforded the desired products in similar yields to those obtained
using complex 2 [15], while tribromide 1c gave lower yields than
2. In particular, the -bromination of acetophenone with 1c
proceeded very poorly, which is possibly due to the low
solubility of the complex in MeOH.

4
Tetrahedron Letters
[5] Y. Nishio, K. Yubata, Y. Wakai, K. Notsu, K. Yamamoto, H.
3. Conclusion
Fujiwara, H. Matsubara, Tetrahedron 75 (2019) 1398–1405.
[6] (a) M. Karki, J. Magolan, J. Org. Chem. 80 (2015) 3701–3707; (b) S.
Song, X. Li, X. Sun, Y. Yuan, N. Jiao, Green Chem. 17 (2015) 3285–
3289.
We successfully performed atom-economical brominations in
which all of the bromine atoms in DITB were consumed and
incorporated into the desired products. In particular, 1.5 equiv. of
an alkene, or 3 equiv. of an arene or a ketone, undergoes
bromination with 1 equiv. of DITB in the presence of an
appropriate oxidant, to afforded the desired product in good
yield. A novel protocol for efficiently monobrominating the -
position of a ketone while suppressing dibromide formation was
also developed. In addition, other tribromide complexes also
participate in atom-economical brominations in this system.
[7] Reviews of HFIP: (a) J.-P. Bégué, D. Bonnet-Delpon, B. Crousse,
Synlett (2004) 18–29; (b) I.A. Shuklov, N.V. Dubrovina, A. Börner,
Synthesis (2007) 2925–2943; (c) I. Colomer, A.E.R. Chamberlain,
M.B. Haughey, T.J. Donohoe, Nature Rev. Chem. 1 (2017) Article
number: 0088.
[8] (a) H.F. Motiwala, R.H. Vekariya, J. Aubé, Org. Lett. 17 (2015) 5484–
5487; (b) G.-X. Li, J. Qu, Chem. Commun. 46 (2010) 2653–2655.
[9] (a) A. Berkessel, M.R.M. Andreae, Tetrahedron Lett. 42 (2001) 2293–
2295; (b) A. Berkessel, M.R.M. Andreae, H. Schmickler, J. Lex,
Angew. Chem. Int. Ed. 41 (2002) 4481–4484.
[10] A, Berkessel, J.A. Adrio, J. Am. Chem. Soc. 128 (2006) 13412–13420.
[11] X. Zeng, S. Liu, G.B. Hammond, B. Xu, ACS Catalysis 8 (2018) 904–
909.
Acknowledgments
[12] The acetonitrile/HFIP ratio used in reference 11 was also employed
here. Increasing the acetonitrile/HFIP ratio from 3:1 to 11:1 (v/v)
lowered the yield of the product to 74%.
[13] The significantly lower isolated yields are the results of difficulties
associated with separating unreacted substrates 6d and 6e from
products 7d and 7e, respectively.
This study was partially supported by JSPS KAKENHI Grant
Number JP16K05755. We acknowledge Tosoh Finechem Corp.
for financial support.
[14] (a) A. Bekaert, O. Provot, O. Rasolojaona, M. Alami, J.-D. Brion,
Tetrahedron Lett. 46 (2005) 4187–4191; (b) W.E. Daniels, E. Chiddix,
S.A. Glickman, J. Org. Chem. 28 (1963) 573–574.
[15] It should be noted that complex 10 is poorly soluble in
dichloromethane or ethanol; this complex is less reactive than complex
2 in some reactions. See reference 5 for details.
References and notes
[1] Reviews of Br2: (a) R. R. Goehring in: L. A. Paquette, D. Crich, P. L.
Fuchs, G. A. Molander (Eds), Encyclopedia of Reagents for Organic
Synthesis, 2nd. Ed., vol. 3, Wiely, Chichester, 2009, pp.1496–1501;
(b) I. Saikia, A.J. Borah, P. Phukan, Chem. Rev. 116 (2016) 6837–
7042.
[2] Reviews of NBS: (a) R.R. Goehring in: L.A. Paquette, D. Crich, P.L.
Fuchs, G.A. Molander (Eds), Encyclopedia of Reagents for Organic
Synthesis, 2nd. Ed., vol. 3, Wiely, Chichester, 2009, pp. 1657–1667;
(b) J.S. Pizey in: Synthetic Reagents, vol. 2, Wiley, New York, 1974,
pp. 1–63; (c) L.F. Fieser, M. Fieser in: Reagents for Organic Synthesis,
vol. 1, Wiely, New York, 1967, pp.78–80.
[3] A review of DDB: B. L. Finkelstein in: L.A. Paquette, D. Crich, P.L.
Fuchs, G.A. Molander (Eds), Encyclopedia of Reagents for Organic
Synthesis, 2nd. Ed., vol. 3, Wiely, Chichester, 2009, pp. 1505–1506.
[4] A review of TBATB: M.J.L. Fournier in: L.A. Paquette, D. Crich, P.L.
Fuchs, G.A. Molander (Eds), Encyclopedia of Reagents for Organic
Synthesis, 2nd. Ed., vol. 11, Wiely, Chichester, 2009, pp. 9135–9136.
Supplementary Material
All compounds prepared in this study are known compounds.
Supplementary data (Tables S1 and S2, Experimental details, 1H
and 13C NMR data of isolated products in this study) can be
found in the online version, at http://

5
Highlights


Atom-economical brominations using
(DMI)2HBr3 with oxidants was demonstrated.
Using this system, olefinic and aromatic
brominations were performed successfully.


Selective α -monobrominations of ketones
also proceeded well.
All of the bromine atoms in the complex were
used to brominate.