Selective Debromination of α,α,α-Tribromomethylketones with HBr–H2O Reductive Catalytic System

Article abstract of DOI:10.1002/ejoc.202001118

A debromination of α,α,α-tribromomethylketones is developed for chemoselective synthesis of α-mono- and α,α-dibromomethylketones with high selectivity under H₂O–HBr reductive conditions. This method offers an efficient and direct way to synthesize α-mono or α,α-dibromomethylketone compounds in high to excellent yields through the process of HBr self-circulation in water.

Full text of DOI:10.1002/ejoc.202001118

Communication
doi.org/10.1002/ejoc.202001118
EurJOC
European Journal of Organic Chemistry
Debromination
Selective Debromination of α,α,α-Tribromomethylketones with
HBr–H2O Reductive Catalytic System
Hui Wang,[a][‡] Meng-Xia Zheng,[a][‡] Hongmei Guo,[b] Guozheng Huang,[b] Zhao Cheng,*[c]
and Abulikemu Abudu Rexit*[a]
Abstract: A debromination of α,α,α-tribromomethylketones is way to synthesize α-mono or α,α-dibromomethylketone com-
developed for chemoselective synthesis of α-mono- and α,α- pounds in high to excellent yields through the process of HBr
dibromomethylketones with high selectivity under H2O–HBr re- self-circulation in water.
ductive conditions. This method offers an efficient and direct
Introduction
explored. Quite recently, Baire et al. used CH3CN/H2O as an
unusual reductive system to synthesize α-iodoacetophenone
compounds (Scheme 1b) from diiodoacetophenones, but the
α-bromoacetophenone product was obtained in very low yield
in this method.[8] Recently our research group also published
related papers (Scheme 1c).[9] Oxidative bromination usually re-
sulted in the unselective introduction of one, two or three
bromine atoms to the substrates in a single step, causing the
subsequent purification difficulties as presented in a lot of syn-
thetic routes. Based on our knowledge, the reductive de-
bromination is also a good method for the preparation of α-
mono- and α,α-dibromomethylketones, which can circumvent
α-Mono- and α,α-dihalomethylketones are important synthetic
intermediates, which are widely applied in the construction
of α,ꢀ-unsaturated ketones or 1,4-diones,[1] ynols,[2] hetero-
cycles,[3] and other small ring compounds.[4] It is also known
that α-mono- and α,α-dihalomethylketone skeletons widely oc-
cur in natural products, pharmaceuticals, agrochemicals and ex-
hibit interesting biological activities, for example, antifungal, an-
tibacterial, anti-HIV, and antitumor (Figure 1).[1,5,6] In particular,
the α-mono- and α,α-dibromomethylketones are of great inter-
est in designing for new drug candidates and agrochemicals
because of its high reactivity and selectivity.
Figure 1. Significant geminal dihalo-compounds.
Traditional preparation of bromides usually induces the
bromine atom of molecular bromine, N-bromosuccinimide, or
other organic bromo-reagents to the substrates (Scheme 1a).[7]
In contrast, the reductive debromination reactions to obtain
monobromo-/dibromo- from tribromo-compounds were less
[a] H. Wang, M.-X. Zheng, Prof. Dr. A. A. Rexit
Department of Chemistry, Xinjiang Normal University,
Urumqi, 830054, China
E-mail: aarexit@xjnu.edu.cn
[b] H. Guo, Prof. Dr. G. Huang
Key Laboratory of Plant Resources and Chemistry of Arid Zone, Xinjiang
Technical Institute of Physics and Chemistry, Chinese Academy of Sciences,
Urumqi, 830011, China
[c] Dr. Z. Cheng
School of Pharmacy, Xi'an Medical University,
Xi'an, 710021, China
[‡] These authors contributed equally to this work
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.202001118.
Scheme 1. The synthesis of α-mono- or α,α-dibromomethylketones.
Eur. J. Org. Chem. 0000, 0–0
1
© 2020 Wiley-VCH GmbH

Communication
doi.org/10.1002/ejoc.202001118
EurJOC
European Journal of Organic Chemistry
this difficulty and obtain the desired mono- or dibromo com- mized yield was achieved when using THF as the solvent
pounds with high purity and yield. (Scheme 1d).[10] Herein, we (Table 1, entry 13). There were no obviously increases in yield
report a selective debromination reaction of α,α,α-tribromo- when treated with less amount of HBr (Table 1, entry 14–17).
methylketones in water with Brønsted acid as a catalyst. In this When the catalytic amount of HBr was 10%, the isolated yield
reaction, α-mono- or α,α-dibromomethylketones can be syn- reached 82% (Table 1, entry 16), which may immensely reduce
thesized selectively in one step by adjusting the amount of HBr the industrial costs and satisfied the mass production. There-
and reaction temperature.
fore, from the optimization of the reaction conditions studies,
it was observed that the desired product α,α-dibromoaceto-
phenone (2a) was obtained in 82 % yield in the presence of
0.3 equivalents 10 % HBr in 1 mL of tetrahydrofuran solvent at
80 °C for 10 h. Furthermore, increasing the reaction temperature
while using less amount of hydrobromide, α,α-dibromoaceto-
phenone 2a would further undergo debromination to be con-
verted into α-bromoacetophenone 3a (Table 1, entry 18). In the
absence of HBr, no reaction occurred (Table 1, entry 20). In a
word, by controlling the amount of HBr and reaction tempera-
ture, the preparation of dibromoacetophenone or mono-
bromoacetophenone was achieved from the same starting ma-
terial.
Results and Discussion
Our inspiration of debromination of α,α,α-tribromomethyl-
ketones originated from the observation of reaction of α,α,α-
tribromoacetophenone and acetic acid in acetonitrile. A small
amount (5 %, Table 1, entry 3) of compound 2a was isolated in
the reaction. Shifting the acid to benzoic acid, p-toluenesulfonic
acid, hydrochloric acid did not improve the yield (Table 1, entry
4–6), while diluted sulfuric acid and nitric acid cannot facilitate
the occurrence of debromination. Delightedly, hydroiodic acid
in acetonitrile improved the yield to 15 % (Table 1, entry 7),
while hydrobromic acid in acetonitrile resulted in the selective
attainment of α,α-dibromoacetophenone 2a in a 76 % yield
(Table 1, entry 8).Other solvents were also screened for this
debromination reaction. It was found that the reaction system
also worked smoothly in acetyl acetate, while 1,2-dichloroeth-
ane and toluene were detrimental to the reaction (Table 1, en-
try 9–11). Compound 2a can be isolated in 55 % yield when
the reaction conducted in ethanol (Table 1, entry 12). The opti-
With the optimized conditions in hand, we next investigated
the scope of substrates in this reductive systems. This new
Table 2. Synthesis of α,α-dibromomethylkenones from tribromomethyl-
ketones.[a,b]
Table 1. Optimization of the reaction conditions.[a]
Entry
Acid (1 equiv.)
Solvent
2a Yield
3a Yield
[%][b]
[%][b]
1
2
3
4
5
6
7
8
H2SO4
HNO3
CH3COOH
PhCOOH
p-CH3C6H4SO3H
HCl
HI
HBr
HBr
HBr
HBr
HBr
HBr
HBr
HBr
HBr
HBr
HBr
HBr
–
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
AcOEt
DCE
toluene
EtOH
THF
THF
THF
no
no
5
6
5
no
no
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
5
15
76
82
7
29
55
92
81
80
82
70
0
9
10
11
12
13
14[c]
15[d]
16[e]
17[f]
18[g]
19[h]
20
THF
THF
THF
THF
85
66
0
15
0
THF
[a] The reactions of 1a (0.10 mmol) and H+ (0.10 mmol) were carried out in
1 mL of solvent at 80 °C for 10 h. [b] Isolated yield. [c] 0.3 equivalents of
40 % HBr. [d] 0.3 equivalents of 20 % HBr. [e] 0.3 equivalents of 10 % HBr.
[f] 0.3 equivalents of 5 % HBr. [g] The reaction was stirred at 120 °C for 2 h,
0.1 equivalents of 10 % HBr. [h] The reaction was stirred at 120 °C for 6 h, 0.1
equivalents of 5 % HBr.
[a] The reactions of 1a (0.10 mmol) and HBr (0.03 mmol, 10 % HBr) were
carried out in 1 mL of THF at 80 °C for 4–12 h. [b] Isolated yield.
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
2
© 2020 Wiley-VCH GmbH

Communication
doi.org/10.1002/ejoc.202001118
EurJOC
European Journal of Organic Chemistry
method turned out to be broadly applicable for tribromomethyl ring of tribromomethylketones 1 were examined (3a–3p). Be-
ketones, such as aromatic, aliphatic, and heterocyclic ketones, sides, various functional groups, such as halides (F, Cl, Br), cy-
almost all of which could give a good yield (Table 2). Mean- ano, trifluoromethyl, and alkyl groups, were introduced into the
while, the position of substituent in these substrates usually did benzene ring. This reductive HBr–H2O route also gave good
not affect the yield.
yields to those substrates, as exampled in the yields of com-
pound 3b (68 %), 3e (90 %), 3f (83 %), 3h (80 %) and 3p (90 %),
respectively.
The electronic and steric effects of different functional
groups on the benzene ring of tribromomethylketones 1 were
examined (2a–2v), which revealed that the substituent groups
In addition, the total debromination of α,α,α-tribromoaceto-
of the benzene in the substrates had no significant effect on phenone also can be achieved with increased reaction tempera-
the yield of target compounds. In addition, a wide range of ture (Scheme 2). It was observed that the target product 4a
functional groups, such as halides (F, Cl, Br), methyl and tri- (56 %) can be obtained at 150 °C in the presence of 0.1 equiva-
fluoromethyl groups, were introduced to different positions of lent 10% HBr.
the benzene ring (2q and 2v). Even for strong electron-with-
drawing groups on the benzene ring, which could affect the
reactive properties of carbonyl groups, this reductive HBr–H2O
route also gave good yields, as observed in the yields of com-
pounds 2f (90 %), 2j (91 %), 2s (90 %), 2u (97 %) and 2v (90 %),
respectively. Moreover, this method could be applied effectively
for aliphatic and heterocyclic substrates, with the good to excel-
Scheme 2. The total debromination of α,α,α-tribromoacetophenone.
lent yields as shown in compounds 2b (90 %), 2c (80 %), 2d
(63 %), and 2e (90 %). Fused aromatic substituted (2s–2t) sub-
strates could also be transformed into the corresponding prod-
Mechanism
ucts with good yields.
Similar applications to a wide scope of substrates were also
observed for α-bromomethylketones (Table 3). The electronic
α,α,α-tribromomethylketone was protonated to provide an in-
and steric effects of different functional groups on the benzene
The proposed reaction mechanism is shown in Figure 2. The
termediate I in acidic condition and resulted in a relatively low
electron density in α-C. The produced Br– during the protona-
tion would combine with the bromine atom located in α-C and
existed as Br2, generating an intermediate II. The intermediate
II was isomerized to furnish the target product. It is noteworthy
that the Br2 produced in the reaction system would react well
with water to generate HBr, which would be capable of catalyz-
ing another round of reaction. Interestingly, hypobromic acid
would also decompose at high temperatures and generate an-
other of HBr, which ensured that a sufficient amount of HBr to
support multiple rounds of HBr–H2O reduction. This hypothesis
reaction mechanism also was supported by the deuterated tar-
get products which were obtained from a reaction carried out
in the presence of DBr/D2O system (Figure 2), (1H-NMR spec-
trum of the crude product, see SI).
Table 3. Synthesis of α-monobromomethylkennes from tribromomethyl-
ketones.[a,b]
[a] The reactions of 1a (0.10 mmol) and HBr (0.01 mmol, 10 % HBr) were
Figure 2. A possible route from α,α,α-tribromomethylketones to α,α-di-
carried out in 1 mL of THF at 120 °C for 4–12 h. [b] Isolated yield.
bromomethylketones.
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
3
© 2020 Wiley-VCH GmbH

Communication
doi.org/10.1002/ejoc.202001118
EurJOC
European Journal of Organic Chemistry
[2] a) J. M. Concellon, H. Rodríguez-Solla, C. Concellon, P. Díaz, Synlett 2006,
Conclusion
6, 837–840; b) C. Peppe, R. P. das Chagas, Synlett 2004, 7, 1187–1190.
[3] a) C. J. Kowalski, K. W. Fields, J. Am. Chem. Soc. 1982, 104, 321–323; b)
L. C. Wang, H. Q. Geng, J. B. Peng, X. F. Wu, Eur. J. Org. Chem. 2020, DOI:
https://doi.org/10.1002/ejoc.202000293.
[4] a) K. Kim, J. Cho, S. C. Yoon, J. Chem. Soc., Perkin Trans. 1 1995, 253–259;
b) P. Maglioli, O. de Lucchi, G. Delogu, G. Valle, Tetrahedron 1992, 48,
365–366; c) M. P. Nemeryuk, M. M. Likhovidova, I. D. Mitsev, T. S. Safon-
ova, Chem. Heterocycl. Compd. (Engl. Transl.) 1986, 22, 468–469.
[5] a) H. Zou, J. Jiang, N. Yi, W. Fu, W. Deng, J. Xiang, Chin. J. Chem. 2016,
34, 1251–1254; b) A. Chandra, K. N. Parida, J. N. Moorthy, Tetrahedron
2017, 73, 5827–5833.
[6] P. Wu, S. Xu, H. Xu, H. Hu, W. Zhang, Tetrahedron Lett. 2017, 58, 618–621.
[7] a) A. Podgorsˇek, S. Stavber, M. Zupan, J. Iskra, Green Chem. 2007, 9,
1212–1218; b) W. Borzęcka, I. Lavandera, V. Gotor, J. Org. Chem. 2013,
78, 7312–7317; c) R. Aeluri, M. Alla, S. Polepalli, N. Jain, Eur. J. Med. Chem.
2015, 100, 18–23; d) Y. Xing, M. Zhang, S. Ciccarelli, J. Lee, B. Catano, Eur.
J. Org. Chem. 2017, 781–784; e) Y. M. Ivon, Y. O. Kuchkovska, Z. V. Voit-
enko, O. O. Grygorenko, Eur. J. Org. Chem. 2020, DOI. https://doi.org/
10.1002/ejoc.202000078.
[8] S. Sadhukhana, B. Bairea, Adv. Synth. Catal. 2018, 360, 298–304.
[9] a) B. Hasimujiang, J. Zeng, Y.-H. Zhang, A. A. Rexit, Synth. Commun. 2018,
48, 887–891; b) Y. Yang, B. Hasimujiang, A. A. Rexit, Chin. J. Org. Chem.
2019, 39, 727–733; c) B. Hasimujiang, Z. Cheng, A. Wusiman, Y. Yang,
A. A. Rexit, ChemistrySelect 2019, 4, 5560–5562.
In summary, in this article, we have developed an efficient de-
bromination reaction of α,α,α-tribromomethylketones with
HBr–H2O as a key reductive catalytic system. In this method,
the α-mono or α,α-dibromomethylketones are synthesized se-
lectively by adjusting the amount of HBr and the reaction tem-
perature in one step reaction. This method features easily acces-
sible starting materials, high chemoselectivity, inexpensive re-
ductive reagent, high to excellent yields, and mild reaction con-
ditions.
Acknowledgments
We are grateful for financial support from Natural Science Foun-
dation of Xinjiang Uygur Autonomous Region of China (No.
2017D01A57).
Keywords: Debromination · Rational product design · Self-
circulation · Green synthesis · Mild reduction
[10] M. D. Rathnayake, J. D. Weaver, Org. Lett. 2019, 21, 9681–9687.
[1] a) Y. Li, T. Mou, L. Lu, X. Jiang, Chem. Commun. 2019, 55, 14299–14303;
b) S. Schwolow, H. Kunz, J. Rheinheimer, T. Opatz, Eur. J. Org. Chem. 2013,
6519–6524.
Received: August 17, 2020
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
4
© 2020 Wiley-VCH GmbH

Communication
doi.org/10.1002/ejoc.202001118
EurJOC
European Journal of Organic Chemistry
Debromination
A debrominationreaction to synthesize
α-mono- and α,α-dibromomethyl-
ketones with high selectivity from
α,α,α-tribromomethylketones by the
controlling of H2OHBr reductive condi-
tions was developed.
H. Wang, M.-X. Zheng, H. Guo,
G. Huang, Z. Cheng,*
A. A. Rexit* ........................................... 1–5
Selective Debromination of α,α,α-
Tribromomethylketones with HBr–
H2O Reductive Catalytic System
doi.org/10.1002/ejoc.202001118
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
5
© 2020 Wiley-VCH GmbH