Facile Approach to Geminal HeterodihalogenationOne-Pot Synthesis of α-Bromo-α-Chloro Ketones

Article abstract of DOI:10.1055/s-0040-1707169

An efficient and practical protocol for the geminal heterodihalogenation of methyl ketones by using readily available dimethyl sulfoxide and a combination of HCl and HBr is reported. Control experiments suggested that the acidity of the solution, as well as the oxidizing ability and nucleophilicity of the dimethyl sulfoxide might work cooperatively in ensuring the success of the tandem substitution. Its operational simplicity, easy accessibility, and mild oxidative conditions suggest that the present strategy might be useful for the assembly of bromochloromethyl functional groups in drug discovery.

Full text of DOI:10.1055/s-0040-1707169

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–E
letter
A
en
J.-f. Zhou et al.
Letter
Synlett
Facile Approach to Geminal Heterodihalogenation.
One-Pot Synthesis of -Bromo--Chloro Ketones
Jin-feng Zhou
O
O
Dong-min Tang
HBr (1.0 equiv)
HCl (4.0 equiv)
DMSO (3.0 equiv)
Br
CH
Ming Bian*
0
0
0
0-
0
0
0
2-2
5
2
1-7
4
7
1
CH3
Ar
Ar
Cl
EtOAc, 30 °C
School of Chemical and Environmental Engineering, Shanghai
Institute of Technology, 100 Haiquan Road, Shanghai 201418,
P. R. China
Mild conditions, high efficiency, one-pot synthesis
Ar groups include naphthyl and 2-thienyl
13 examples, up to 65–81% yield
bianming@sit.edu.cn
Received: 30.03.2020
Accepted after revision: 04.06.2020
Published online: 01.07.2020
nation, require electrophilic halogen sources that are typi-
cally toxic and harmful to the environment. Various modi-
fied reagents, mostly with polyamide backbones, such as
NBS and NCS have been used, but these reactions tend to
involve laborious workup and low atom efficiency.5 On the
other hand, although frequently employed in nature, inor-
ganic halogen salts, particularly hydrogen halides (as by-
products of dihalogen-based halogenations), are inactive
unless used with strong oxidants,6 which makes them in-
compatible with sensitive functional groups in practical ap-
proaches. Despite a few recent reports,7 good performance
is rarely attained in mimicking mild natural halogenation
processes with common halides, let alone in geminal het-
erodihalogenation.8
DOI: 10.1055/s-0040-1707169; Art ID: st-2020-u0174-l
Abstract An efficient and practical protocol for the geminal heterodi-
halogenation of methyl ketones by using readily available dimethyl sulf-
oxide and a combination of HCl and HBr is reported. Control experi-
ments suggested that the acidity of the solution, as well as the oxidizing
ability and nucleophilicity of the dimethyl sulfoxide might work cooper-
atively in ensuring the success of the tandem substitution. Its opera-
tional simplicity, easy accessibility, and mild oxidative conditions sug-
gest that the present strategy might be useful for the assembly of
bromochloromethyl functional groups in drug discovery.
Key words heterodihalogenation, dimethyl sulfoxide, bromochloro-
methyl ketones, tandem reaction
O
Enzymatic incorporation of halogens into a diverse ar-
ray of molecular scaffolds has been widely used in nature as
an evolutionary strategy for the formation of bioactive sec-
ondary metabolites.1 Inspired by nature, synthetic endeav-
ors to create such bioavailable organohalides for pharma-
ceutical and agrochemical applications, as well as for other
valuable materials, continue to receive increasing atten-
tion.2 Among these halogenated species, geminal diha-
lomethyl compounds are of great significance. For example,
nowadays, simple ,-dichloroacetophenone is used to in-
hibit the activity of pyruvate dehydrogenase kinase 1, an
important target in cancer studies,3 and halothane (1-bro-
mo-1-chloro-2,2,2-trifluoroethane) was one of the first ha-
logenated nonflammable inhalable anesthetics to replace
diethyl ether (Figure 1).4
O
P
O
P
O
P
NH
HO
O
O
O
OH
N
O
O
OH OH
Cl
Cl
O
Cl
OH
Cl
α,α-dichloroacetophenone
β-D-2'-deoxy-2'-dichlorouridine
inhibitor of hepatitis C virus (HCV)
antibacterial
Br
OSO3H
Br
Br
X
Me
X
Br
Br
Br
geminal dihalomethylene
HO3SO
bromodanicalipin A
(more toxic against brine shrimps)
H
N
Cl
S
I
Me
Me
Given the critical importance of geminal dihalogenated
molecules in life-science-related fields, simple and highly
tolerant synthetic methods are desperately needed. Many of
the conventional methods, especially for aromatic haloge-
CHBrClCF3
O
CO2CH2OPiv
antibacterial
halothane
(anesthesia)
Figure 1 Significant geminal dihalomethyl compounds
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
J.-f. Zhou et al.
Letter
Synlett
Dimethyl sulfoxide (DMSO), a classic aprotic polar com-
pound, is not only widely used as a cheap and versatile sol-
vent with low toxicity,9 but also displays versatility in many
well-known named reactions as an essential oxidant10 or as
a potential oxygen source.11 When combined with aqueous
HBr, DMSO displays a good oxidizing ability in the bromina-
tion of several synthetic building blocks.11d,11e,12 More re-
cently, Jiao’s group have demonstrated some attractive ap-
plications of this protocol in which the low cost of DMSO
was exploited along with a high bromide atom economy.13
Essentially, the critical bromide cations were hypothesized
to be generated in situ from DMSO and HBr.14 However,
other hydrogen halides, especially the common reagent
HCl, appeared to fail in this DMSO-based system.15 On the
basis that a chlorodimethylsulfonium species has been
identified in the Swern oxidative process, we speculated
that similar transformations might also be realized. Here,
we introduce a simple approach to the DMSO-based oxida-
tive geminal heterodihalogenation of methyl ketones.
Our initial study began with attempts to chlorinate ace-
tophenone (1a) by employing a DMSO-based oxidative
strategy. Clearly, no chlorinated products were detected in
the case of simple replacement (Table 1, entry 1), in a man-
ner consistent with previous studies.12b,13,14a It was interest-
ing to find that when the reaction was carried out in a mix-
ture of aqueous HBr and HCl, geminal heterodihalogenation
occurred in a tandem process to give the -bromo--chloro
ketone 2a in 20% isolated yield. (entry 2). A lower tempera-
ture and an increase in the amount of DMSO suppressed the
undesired dibromination process, but gave a lower yield of
2a (entry 3). A promising conversion was achieved by treat-
ment with 1.0 equivalent of HBr, 4.0 equivalents of HCl, and
3.0 equivalents of DMSO as the oxidant in EtOAc at 30 °C.
(entries 4). Neither the use of other common source of
chloride (NaCl or TMSCl; entries 5 and 6) nor changing the
solvent (entry 7) resulted in any improvement in the reac-
tion outcome. As expected, the use of p-toluenesulfonic
acid monohydrate as a proton source with the correspond-
ing inorganic chloride and bromide salts also give 2a, albeit
in a rather lower yield. (entry 8). Moreover, the tandem
substitution also proceeded smoothly with bulky diphenyl
sulfoxide (entry 9).
Table 1 Optimization of the Geminal Heterodihalogenation
O
O
HBr 1.0 equiv
DMSO, Cl-source
CH3
CHBrCl
EtOAc, air
2a
1a
Entry Modification of conditions
Time
(h)
Yielda
(%) of 2a
1
2
HCl (2.0 equiv), no HBr
48
3
NDb
20c
HCl (2.0 equiv), EtOAc, 60 °C
3
HCl (2.0 equiv), DMSO (2.0 equiv), 30 °C
HCl (4.0 equiv), DMSO (3.0 equiv) at 30 °C
NaCl instead of HCl
10
15
24
3
10d
70e
NDf
66
4
5
6
TMSCl instead of HCl with drops of H2O
THF, CH2Cl2, iPrOH, or HMPA instead of EtOAc
7
15
40–56
12g
66
8
TsOH·H2O, NaBr, and NaCl instead of HBr and HCl 15
9
Ph2SO instead of DMSO
No Cl source
15
48
h
10
–
a Isolated yield after flash chromatography.
b No chlorinated compound was detected.
c 15% of dibromide + 60% of monobromide
d 25% of dibromide + 40% of monobromide.
e 9% of dibromide + 4% of monobromide
f 50% of monobromide + 25% of dibromide; no heterodihalogenated prod-
uct was detected.
g 56% of monochloride as the major product.
h 20% of dibromide + 20% of monobromide + 40% of sulfonium bromide.
usually occurs in other oxidative processes,17 was not de-
tected in the present system (entries 10 and 11). Addition-
ally, compounds with fused aromatic rings (2l) and hetero-
cyclic compounds (2m) were also converted. However, the
heterodihalogenation did not occur with ketones with lon-
ger alkyl chains, such as propiophenone (1n) or 4-phenyl-
butan-2-one (1o).
Further studies were carried out to identify the mecha-
nism of this geminal bromochlorination. The dibromide is
probably a key intermediate in the process. Notably, on
treatment of compound 3 with aqueous HCl–EtOAc solu-
tion, the tandem conversion to 2a did not occur unless
DMSO was added. (Scheme 1, equation 1). Moreover, the
transformation from the sulfonium bromide 4, a common
byproduct in the HBr–DMSO strategy,18 also failed to pro-
ceed (Scheme 1, equation 2).
By using the optimized conditions, we then explored
the generality of this strategy.16 For the bromochlorination,
the presence of electron-donating or electron-withdrawing
functional groups on the aromatic rings seemed to have lit-
tle effect; all compounds showed excellent conversion rates
and moderate yields (Table 2, entries 1–6). Transformable
methoxy (2c), trifluoromethyl (2e), and halo (2f) groups
were all tolerated. Furthermore, compounds with an anchi-
meric effect were also successfully transformed under these
mild conditions (entries 7 and 8). Steric hindrance by sub-
stituents (2h and 2i) did not affect the efficiency of the re-
action. Notably, halogenation at a benzylic position, which
O
Eq. 1
2a
Ph
O
CHBr2
3
Conditions: 1) HCl-DMSO: 88%
2) only HCl:
none
HCl-DMSO
Eq. 2
2a
Ph
CHSMe2 Br
4
Scheme 1 Control experiments for the mechanism
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

C
J.-f. Zhou et al.
Letter
Synlett
Table 2 (continued)
Table 2 Scope of Substrates
Entry
Product
Conversion (%) Yielda (%)
O
O
HBr (1.0 equiv)
HCl (4.0 equiv)
DMSO (3.0 equiv)
O
O
CH3
CHBrCl
R
Cl
R
13
2m
2n
2o
90
–
67
EtOAc, 30 °C, Ar
1
2
S
Br
Br
Entry
1
Product
Conversion (%) Yielda (%)
14
15
NDb
NDc
O
Cl
Cl
O
2a
92
95
70
73
O
Br
Br
–
Ph
Cl
Cl
2
3
4
5
2b
a Isolated yield after flash chromatography.
b 40% of monobromide.
Br
Me
c 20% of monobromide.
O
Cl
2c
94
90
96
74
65
81
The mechanism is not yet completely clear. However, on
the basis of the control experiments described above, a pos-
sible process for this tandem heterodihalogenation is pro-
posed, as shown in Scheme 2. First, due to the strong acidi-
ty, a possible active bromonium species I is generated by
protonation of DMSO and reacts with the ketone to provide
the dibrominated species 3. A complex active cation II is
next formed by nucleophilic attack of excess DMSO, along
with removal of one bromide ion.11g,19 The higher concen-
tration of chloride anions might facilitate a second nucleo-
philic attack at the back of C–O bond adjacent to the car-
bonyl group to furnish the desired geminal bromochlori-
nated product.
Br
MeO
O2N
O
Cl
2d
Br
O
Cl
2e
Br
F3C
Br
O
Cl
6
7
2f
92
92
90
95
94
72
75
72
75
73
Br
F
F
O
Me
Me
O
O
O
Br
S
O
1a
O
Br
S
Ph
Me
CH3
Cl
Cl
Cl
O
2g
2h
2i
Ph
CH
Ph
CHBr2
Me
Cl
Br
Br
Br
Br
I
3
II
OH
Me
DMSO
8
H
Br
O
O
S
Cl
Ph
CH
Br
Me
Me
9
(DMSO)
2a
Scheme 2 Proposed reaction mechanism
O
Cl
10
2j
In conclusion, we have developed a simple one-pot ap-
proach for the geminal heterodihalogenation of methyl ke-
tones by using a simple combination of HBr, HCl, and DM-
SO. Besides the acidity in the reaction, the oxidizing ability
and nucleophilicity of dimethyl sulfoxide might be of im-
portance in furnish a sulfonium species that permits the
tandem transformation. Advantages of this chemistry in-
clude its safety, simplicity, and the cheapness of its re-
agents; moreover, it provides an efficient method for as-
sembling inaccessible heterodihalomethyl moieties on nu-
Br
Et
O
Cl
11
12
2k
2l
91
92
71
72
Br
Ph
O
Cl
Br
Thieme. All rights reserved. Synlett 2020, 31, A–E

D
J.-f. Zhou et al.
Letter
Synlett
merous biologically relevant molecules. Studies on further
applications of this methods and the stereochemistry of the
transformation are ongoing in our laboratory.
691. (c) Hashem, A.; Khan, M. A. E. J. Bangladesh Chem. Soc.
2007, 20, 1. (d) Kazutaka, S.; Akira, N.; Yoshinori, S.; Tsubasa,
M.; Seiji, I. Org. Lett. 2011, 13, 2944. (e) Shariff, N.; Mathi, S.;
Rameshkumar, C.; Emmanuvel, L. Tetrahedron Lett. 2015, 56,
934. (f) Gallo, R. D. C.; Ahmad, A.; Metzker, G.; Burtoloso, A. C. B.
Chem. Eur. J. 2017, 23, 16980. (g) Mazenauer, M.; Manov, S.;
Galati, V.; Kappeler, P.; Stohner, J. RSC Adv. 2017, 7, 55434.
(h) Naruse, A.; Kitahara, K.; Iwasa, S.; Shibatomi, K. Asian J. Org.
Chem. 2019, 8, 691. (i) Kitahara, K.; Mizutani, H.; Iwasa, S.;
Shibatomi, K. Synthesis 2019, 51, 4385.
Funding Information
We are grateful to the NSFC (21302204) for financial support.
N
ati
o
n
a
lNaturalS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
C
h
i
n
a
(2
1
3
0
2
2
0
4)
(9) Martin, D.; Weise, A.; Niclas, H. J. Angew. Chem. Int. Ed. Engl.
1967, 6, 318.
(10) For selected reviews, see: (a) Epstein, W.; Sweat, F. Chem. Rev.
1967, 67, 247. (b) Tidwell, T. T. Synthesis 1990, 857.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707169.
S
u
p
p
orti
n
gInformati
o
n
S
u
p
p
orit
n
gInformati
o
n
(11) (a) Kornblum, N.; Powers, J. W.; Anderson, G. J.; Jones, W. J.;
Larson, H. O.; Levand, O.; Weaver, W. M. J. Am. Chem. Soc. 1957,
79, 6562. (b) Tomita, R.; Yasu, Y.; Koike, T.; Akita, M. Angew.
Chem. Int. Ed. 2014, 53, 7144. (c) Mupparapu, N.; Khan, S.;
Battula, S.; Kushwaha, M.; Gupta, A. P.; Ahmed, Q. N.;
Vishwakarma, R. A. Org. Lett. 2014, 16, 1152. (d) Wu, X.; Gao, Q.;
Liu, S.; Wu, A. Org. Lett. 2014, 16, 2888. (e) Gao, Q.; Wu, X.; Liu,
S.; Wu, A. Org. Lett. 2014, 16, 1732. (f) Ashikari, Y.; Nokami, T.;
Yoshida, J.-i. J. Am. Chem. Soc. 2011, 133, 11840. (g) Ashikari, Y.;
Nokami, T.; Yoshida, J.-i. Org. Lett. 2012, 14, 938. (h) Xu, R.; Wan,
J.-P.; Mao, H.; Pan, Y. J. Am. Chem. Soc. 2010, 132, 15531; corri-
gendum: J. Am. Chem. Soc. 2011, 133: 387. (i) Ashikari, Y.;
Nokami, T.; Yoshida, J.-i. Org. Biomol. Chem. 2013, 11, 3322.
(j) Mori, S.; Takubo, M.; Yanase, T.; Maegawa, T.; Monguchi, Y.;
Sajiki, H. Adv. Synth. Catal. 2010, 352, 1630.
(12) (a) Floyd, M. B.; Du, M. T.; Fabio, P. F.; Jacob, L. A.; Johnson, B. D.
J. Org. Chem. 1985, 50, 5022. (b) Liang, Y.-F.; Wu, K.; Song, S.; Li,
X.; Huang, X.; Jiao, N. Org. Lett. 2015, 17, 876. (c) Li, H.-L.; An, X.-
L.; Ge, L.-S.; Luo, X.; Deng, W.-P. Tetrahedron 2015, 71, 3247. For
I2-mediated reactions, see: (d) Kale, A.; Bingi, C.; Ragi, N. C.;
Sripadi, P.; Tadikamalla, P. R.; Atmakur, K. Synlett 2017, 1603.
(e) Wu, X.; Gao, Q.; Lian, M.; Liu, S.; Wu, A. RSC Adv. 2014, 4,
51180. (f) Yin, G.; Zhou, B.; Meng, X.; Wu, A.; Pan, Y. Org. Lett.
2006, 8, 2245; see also Refs. 11 (d) and 11 (e).
(13) (a) Song, S.; Huang, X. Q.; Liang, Y.-F.; Tang, C. H.; Li, X. W.; Jiao,
N. Green Chem. 2015, 17, 2727. (b) Song, S.; Li, X.; Sun, X.;
Yuana, Y.; Jiao, N. Green Chem. 2015, 17, 3285. (c) Song, S.; Sun,
X.; Li, X. W.; Yuan, Y. Z.; Jiao, N. Org. Lett. 2015, 17, 2886.
(14) (a) Majetich, G.; Hicks, R.; Reister, S. J. Org. Chem. 1997, 62,
4321. For selected recent applications, see: (b) Taylor, C. A.;
Zhang, Y. A.; Snyder, S. A. Chem. Sci. 2020, 11, 3036. (c) Zhang,
Y.-A.; Yaw, N.; Snyder, S. A. J. Am. Chem. Soc. 2019, 141, 7776.
(d) Shen, M.; Kretschmer, M.; Brill, Z. G.; Snyder, S. A. Org. Lett.
2016, 18, 5018. (e) Ke, Z.; Tan, C. K.; Chen, F.; Yeung, Y.-Y. J. Am.
Chem. Soc. 2014, 136, 5627. (f) Ashikari, Y.; Shimizu, A.; Nokami,
T.; Yoshida, J.-i. J. Am. Chem. Soc. 2013, 135, 16070. (g) Bonney,
K. J.; Braddock, D. C. J. Org. Chem. 2012, 77, 9574. (h) Stefan, E.;
Taylor, R. E. Org. Lett. 2012, 14, 3490. (i) Synder, S. A.; Treitler, D.
S.; Brucks, A. P.; Sattler, W. J. Am. Chem. Soc. 2011, 133, 15898.
(j) Synder, S. A.; Treitler, D. S. Org. Synth. 2011, 88, 54.
(k) Snyder, S. A.; Treitler, D. S.; Brucks, A. P. J. Am. Chem. Soc.
2010, 132, 14303. (l) Synder, S. A.; Gollner, A.; Chiriac, M. I.
Nature 2011, 474, 461. (m) Synder, S. A.; Treitler, D. S. Angew.
Chem. Int. Ed. 2009, 48, 7899.
References and Notes
(1) For recent reviews, see: (a) Vaillancourt, F. H.; Yeh, E.; Vosburg,
D. A.; Garneau-Tsodikova, S.; Walsh, C. T. Chem. Rev. 2006, 106,
3364. (b) Butler, A.; Sandy, M. Nature 2009, 460, 848.
(c) Latham, J.; Brandenburger, E.; Shepherd, S. A.; Menon, B. R.
K.; Micklefield, J. Chem. Rev. 2018, 118, 232.
(2) Landry, M. L.; Burns, N. Z. Acc. Chem. Res. 2018, 51, 1260.
(3) (a) Qin, L.; Tian, Y.; Yu, Z.; Shi, D.; Wang, J.; Zhang, C.; Peng, R.;
Chen, X.; Liu, C.; Chen, Y.; Huang, W.; Deng, W. Oncotarget
2016, 7, 1395. (b) Xu, B.; Yu, Z.; Xiang, S.; Li, Y.; Zhang, S.-L.; He,
Y. Eur. J. Med. Chem. 2018, 155, 275.
(4) Halpern, D. F. In Organofluorine Chemistry: Principles and Com-
mercial Applications; Banks, R. E.; Smart, B. E.; Tatlow, J. C., Ed.;
Plenum Press: New York, 1994, Chap. 25 543.
(5) For a recent review, see: (a) Vekariya, R. H.; Patel, H. D. Tetrahe-
dron 2014, 70, 3949. For a recent application, see: (b) Nishii, Y.;
Ikeda, M.; Hayashi, Y.; Kawauchi, S.; Miura, M. J. Am. Chem. Soc.
2020, 142, 1621.
(6) For a review, see: (a) Podgoršek, A.; Zupan, M.; Iskra, J. Angew.
Chem. Int. Ed. 2009, 48, 8424. For selected oxidative bromina-
tions, see: (b) Zhang, G.; Liu, R.; Xu, Q.; Ma, X.; Liang, X. Adv.
Synth. Catal. 2006, 348, 862. (c) Podgoršek, A.; Stavber, S.;
Zupan, M.; Iskra, J. Green Chem. 2007, 9, 1212. (d) Adimurthy, S.;
Ghosh, S.; Patoliya, P. U.; Ramachandraiah, G.; Agrawal, M.;
Gandhi, M. R.; Upadhyay, S. C.; Ghosh, P. K.; Ranu, B. C. Green
Chem. 2008, 10, 232. (e) Yang, L.; Lu, Z.; Stahl, S. S. Chem.
Commun. 2009, 6460. (f) Podgoršek, A.; Eissen, M.; Fleckenstein,
J.; Stavber, S.; Zupan, M.; Iskra, J. Green Chem. 2009, 11, 120.
(g) Pandit, P.; Gayen, K. S.; Khamarui, S.; Chatterjee, N.; Maiti, D.
K. Chem. Commun. 2011, 47, 6933. (h) Yonehara, K.; Kamata, K.;
Yamaguchi, K.; Mizuno, N. Chem. Commun. 2011, 47, 1692.
(i) Wang, G.-W.; Gao, J. Green Chem. 2012, 14, 1125. (j) Gu, L.; Lu,
T.; Zhang, M.; Tou, L.; Zhang, Y. Adv. Synth. Catal. 2013, 355,
1077. (k) Yu, T.-Y.; Wang, Y.; Hu, X.-Q.; Xu, P.-F. Chem. Commun.
2014, 50, 7817. (l) Prebil, R.; Stavber, S. Adv. Synth. Catal. 2014,
356, 1266.
(7) (a) Hering, T.; Mühldorf, B.; Wolf, R.; König, B. Angew. Chem. Int.
Ed. 2016, 55, 5342. (b) Hering, T.; Meyer, A. U.; König, B. J. Org.
Chem. 2016, 81, 6927. (c) Yuan, Y.; Yao, A.; Zheng, Y.; Gao, M.;
Zhou, Z.; Qiao, J.; Hu, J.; Ye, B.; Zhao, J.; Wen, H.; Lei, A. iScience
2019, 12, 293. (d) Li, Y. M.; Mou, T.; Liu, L. L.; Jiang, X. F. Chem.
Commun. 2019, 55, 14299.
(8) For selected geminal heterodihalogenations, see: (a) Pfab, J. Tet-
rahedron Lett. 1976, 17, 943. (b) Barluenga, J.; Fernández-Simón,
J.; Concellón, J. M.; Yus, M. J. Chem. Soc., Perkin Trans 1 1989,
(15) (a) Sorabad, G. S.; Maddani, M. R. Asian J. Org. Chem. 2019, 8,
1336. (b) Demertzidou, V. P.; Pappa, S.; Sarli, V.; Zografos, A.
J. Org. Chem. 2017, 82, 8710.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

E
J.-f. Zhou et al.
Letter
Synlett
(16) 2-Bromo-2-chloro-1-phenylethanone (2a); Typical Proce-
dure
1H NMR (500 MHz, CDCl3):  = 8.08 (d, J = 7.4 Hz, 2 H), 7.65 (t, J =
7.8 Hz, 1 H), 7.52 (t, J = 7.8 Hz, 2 H), 6.77 (s, 1 H). 13C NMR (125
MHz, CDCl3)  = 186.01, 134.55, 131.18, 129.65, 128.96, 54.18.
HRMS(EI): m/z [M + Na]+ calcd for C8H6BrClNaO: 256.9162;
found: 256.9158.
Acetophenone (1a; 1.0 mmol), DMSO (234.4 mg, 3.0 mmol),
38% aq HCl (145.8 mg, 4.0 mmol), and 40% aq HBr (202.3 mg,
1.0 mmol) were combined in EtOAc (3.0 mL) under air, and the
mixture was stirred for 15 h at 30 °C while the reaction was
monitored by TLC. The mixture was then dried (MgSO4) and
concentrated in vacuum, and the residue was purified by flash
column chromatography (silica gel, PE–EtOAc) to give a white
solid; yield: 163.1 mg (70%); mp 37-40 °C; Rf = 0.55 (PE–EtOAc,
30:2).
(17) Inagaki, M.; Matsumoto, S.; Tsuri, T. J. Org. Chem. 2003, 68, 1128.
(18) Cao, Z.; Shi, D.; Qu, Y.; Tao, C.; Liu, W.; Yao, G. Molecules 2013,
18, 15717.
(19) (a) Bauer, D. P.; Macomber, R. S. J. Org. Chem. 1975, 40, 1990.
(b) Kornblum, N.; Jones, W. J.; Anderson, G. J. J. Am. Chem. Soc.
1959, 81, 4113.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E