Switchable Synthesis of α,α-Dihalomethyl and α,α,α-Trihalomethyl Ketones by Metal-Free Decomposition of Enaminone C=C Double Bond

Article abstract of DOI:10.1002/adsc.201901234

The novel free radical-based cleavage of the enaminone C=C double bond is realized by using N-halosuccinimides (NXS) in the presence of benzoyl peroxide (BPO) with mild heating, enabling the tunable synthesis of α,α-dihalomethyl ketones and α,α,α-trihalomethyl ketones under different reaction conditions. The formation of these divergent products involving featured C=C double bond cleavage requires no any metal reagent, and represents one more practical example on the synthesis of poly halogenated methyl ketones via the functionalization of carbon?carbon bond. (Figure presented.).

Full text of DOI:10.1002/adsc.201901234

Title: Switchable Synthesis of α,α-Dihalomethyl and α,α,α-
Trihalomethyl Ketones by Metal-Free Decomposition of
Enaminone C=C Double Bond
Authors: Yunyun Liu, Jin Xiong, Li Wei, and Jie-Ping Wan
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901234
Link to VoR: http://dx.doi.org/10.1002/adsc.201901234

10.1002/adsc.201901234
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201901234
Switchable Synthesis of α,α-Dihalomethyl and α,α,α-
Trihalomethyl Ketones by Metal-Free Decomposition of
Enaminone C=C Double Bond
Yunyun Liu,a* Jin Xiong,a Li Weia and Jie-Ping Wana*
a
College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, P. R. China
Tel:/Fax: +86 791 8812 0380; E-mail: chemliuyunyun@jxnu.edu.cn; wanjieping@jxnu.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. The novel free radical-based cleavage of the cleavage requires no any metal reagent, and represents one
enaminone C=C double bond is realized by using N- more practical example on the synthesis of poly
halosuccinimides (NXS) in the presence of benzoyl peroxide halogenated methyl ketones via the functionalization of
(BPO) with mild heating, enabling the tunable synthesis of carbon-carbon bond
.
α,α-dihalomethyl ketones and α,α,α-trihalomethyl ketones
under different reaction conditions. The formation of these
divergent products involving featured C=C double bond
Keywords: Enaminone; C=C bond cleavage; Switchable;
α,α-Dihalomethyl ketone; α,α,α-Trihalomethyl ketone
ketones. On the contrary, α,α,α-trihalommethyl
ketones can be accessed by the oxidation of α,α,α-
Introduction
trihalomethyl
alcohols,[11]
of propiolic
decarboxylative
Due to the presence of gem-dihalogen and
trihalogen atoms in the ketone α-site, the α,α-
dihalomethyl ketones and α,α,α-trihalomethyl ketones
possess exceptionally rich pathways of organic
transformation, and have thus exhibited widespread
applications in organic synthesis. Typically, as key
starting materials, α,α-dihalomethyl ketones can be
used for efficient synthesis of ketones with various α-
functional structure,[1] heterocycles,[2] and other
acyclic products with attractive application
potential.[3] On the other hand, α,α,α-trihalomethyl
ketones are particularly important precursors for the
synthesis of α-aminoamides, haloalkenes, esters,
amides and functionalized chiral alcohols etc.[4] Not
surprisingly, owing to the high usefulness of these di-
and trihalogenated methyl ketones, the synthetic
research towards these compounds has accordingly
received tremendous attention. As earliest efforts, the
di- and trihalogenation on the C(sp3)-H bonds in
methyl ketones are used for the synthesis of α,α-
trihalogenation
acids,[12]
and
halogenation of α,α-dihalomethyl ketones.[13] Overall,
the methods for the synthesis of these gem-
halogenated ketones are yet rare. In addition, one or
more of the restrictions such as the employment of
sensitive reagents, reliance to noble metal catalysts,
formation of mixed mono-, di- and trihalogenated
products, and/or limited tolerance to single halogen
species encountered in the known methods implies
the urgent requirement to develop more
complementary tactics for the practical synthesis of
both
α,α-dihalomethyl
ketones
and
α,α,α-
trihalomethyl ketones.
Over the recent years, the synthetic research based
on enaminone platform has won splendid advances
by providing numerous organic products via a broad
array of distinctive transformation models.[14]
Particularly, based on the previously disclosed results
by us and others, the transition metal-free
functionalization of the enaminone vinyl C=C double
dihalomethyl ketones and α,α,α-trihalomethyl ketones, bond cleavage has been identified as highly beneficial
respctively.[5] In the journey of expanding more
accesses to these useful products, a plethora of
different tactics have been successively established.
For example, the dihalooxygenation of alkynes and
alkenes,[6] selective reduction of α,α,α-trihalomethyl
ketones,[7] the C-H halogenation of α-haloketones,[8]
the α,α-dihalogenation of sulfoxonium ylides,[9] as
well as the transformations on a few other
functionalized precursors,[10] have been developed as
applicable protocols towards α,α-dihalomethyl
strategy in the synthesis of many valuable chemical
products such as α-ketoesters,[15] ketones with α-
heteroatom functionalization,[16] α-ketoamides and
thioamides,[17]
aminocarbonyl
functionalized
enamines,[18] 1,4-ketoaldehydes,[19] and vincinal
diketones.[20] Notably, a common feature in most of
these carbon-carbon bond cleavage is the initiation of
free radical species, which indicates that free radical
generation is a reliable way to design more divergent
synthetic methods by cleaving the enaminone C=C
1
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10.1002/adsc.201901234
Advanced Synthesis & Catalysis
double bond. Therefore, considering the easy
generation of halogen free radical from many
commercial halogen reagents, we envisage that the
synthesis of ketones bearing functional α-haloatom
such as α,α-dihalomethyl ketones and α,α,α-
trihalomethyl ketones can be accessed by scissoring
the carbon-carbon in the readily available
enaminones via free radical pathway. In combination
with the usefulness of gem-halogenated compounds[21]
as well as the advantage of carbon-carbon bond
functionalization in organic synthesis,[22] we report
herein the unprecedented methods for the tunable
synthesis of both α,α-dihalomethyl ketones and α,α,α-
trihalomethyl ketones by cleaving the enaminone
C=C double bond with free radical transformation
under totally metal-free conditions.
11c)
12d)
13
BPO
BPO
BPO
BPO
BPO
BPO
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
60
60
rt
50
70
60
65
68
37
60
67
trace
14
15
16e)
a)
General conditions：1a (0.3 mmol), 2a (0.6 mmol),
b)
peroxide (0.15 mmol), in solvent (2 mL), stirred for 12 h.
c)
d)
Isolated yield based on 1a. BPO (0.09 mmol). BPO
(0.27 mmol). e) In the presence of TEMPO (2 equiv).
Following the experiments optimizing reaction
conditions, the scope of this C=C bond cleavage
protocol has been examined on the synthesis of
dihaloketones 3. As given in Table 2, the titled
reaction exhibited excellent tolerance to the synthesis
of dibromomethyl- and dichloromethyl ketones 3 by
employing NXS (X = Br and Cl) as the halogen
sources (Table 2). Generally, most of the
dichlorinated products were acquired with slightly
lower yield than equivalent dibrominated products
(3a-3d, 3f-3i, 3l-3m and 3o-3p, Table 2). On the
other hand, enaminones bearing different functional
groups in the phenyl ring, including those in para-
position (3c-3j, Table 2), ortho-position (3k-3n,
Table 2) and meta-position (3o-3p, Table 2), as well
as substrates with disubstitution (3r-3s, Table 2)
practically reacted with NXS to give corresponding
products with generally good yields regardless the
position and property of the substituent. Moreover,
fused aryl (3t, Table 2) and heteroaryl (3u-3w, Table
2) also participated the reaction to provide diverse
aryl functionalized α,α-dihaloketones with good
results, illustrating the excellent application scope of
the method in synthesizing α,α-dihaloketones. Using
N-iodosuccinimide (NIS) as halogen source, however,
didn’t provide the expected diiodinated methyl
ketones.
Results and Discussion
To initiate the work, the N,N-dimethyl enaminone
1a and N-bromosuccinimide (NBS) 2a were selected
for probing the reaction conditions. Simply heating
the two reactants under air atmosphere gave the
dibrominated ketone 3a with moderate yield. While
peroxide has been known to be able to promote the
free radical reactions,[23] we then employed different
commercial peroxides such as BPO, H2O2, TBHP and
DTBP to the reaction, whereby significant
improvement on the yield of 3a was acquired in the
entry with BPO (entries 2-5, Table 1). Subsequent
comparison on the effect of medium individually
using DMF, DMSO, MeCN, benzene and
cyclohexane proved that the nonpolar p-xylene was a
better medium for this reaction (entries 6-10, Table 1).
On the other hand, varying the loading of BPO led to
decreased yield of 3a (entries 11-13, Table 1).
Furthermore, conducting the reaction at different
o
temperatures indicated that 60 C was the proper
temperature (entries 13-15, Table 1). Finally, a
control experiment in the presence of TEMPO (2
equiv) gave only trace product, suggesting that this
reaction proceeded via key free radical intermediates
(entry 16, Table 1).
Table 2 Scope on the synthesis of α,α-dihaloketonesa,b)
Table 1 Condition optimization on the reaction providing
α,α-dibromoketonea)
entry peroxide
solvent
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
DMF
DMSO
MeCN
benzene
T (oC)
60
60
60
60
60
60
60
60
yield (%)b)
1
-
48
77
40
35
29
36
30
35
61
40
2
3
4
5
6
7
8
9
BPO
H2O2
TBHP
DTBP
BPO
BPO
BPO
BPO
BPO
60
10
cyclohexane 60
2
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10.1002/adsc.201901234
Advanced Synthesis & Catalysis
a)
Reaction conditions: enaminone 1 (0.3 mmol), NXS 2
4a could be practically acquired in gram scale by
properly performing the reaction in lager scale
(Scheme 2).
(0.6 mmol), BPO (0.15 mmol) in p-xylene (2 mL), stirred
at 60 C for 12 h under air atmosphere. b) Isolated yield
o
based on 1.
In the further efforts, we expected to switch the
reaction pathway to provide different halogenated
products. Excitingly, when the loading of NBS was
increased and the reaction medium was changed into
toluene (the reaction in p-xylene provide 4a with 28%
yield), the selective α,α,α-tribromomethyl ketones 4
was achieved (Scheme 1). Analogously, the synthesis
of the tribromomethyl ketones employing aryl
functionalized enaminones containing enriched
substructures was also practical. For example, the
enaminones with alkyl, alkoxyl and halogen
functionalized phenyl in para-(4a-4f, Scheme 1),
ortho-(4g, Scheme 1) and meta-sites (4h-4i, Scheme
1), the disubstituted phenyl enaminone (4j, Scheme
1) were all successfully employed. More notably, the
heteroaryl, such as thiophene and furan
functionalized enaminones could also be transformed
into the target products (4l-4n, Scheme 1). The
products in this section were obtained with generally
good yield, and no notable impact of the functional
group in the aryl fragment to the reaction was
observed. On the other hand, it should be noted that
attempts in employing NCS and NIS under the
present conditions for the synthesis of equivalent
trichloro- and triiodomethyl ketones were not
successful. For the reaction of NCS, only low
transformation providing dichloromethyl ketone 3b
was observed under the present conditions. Notably,
the individual selectivity in the synthesis of both
dihalo- and trihalomethyl ketones were excellent
since the undesired side product(s) were not observed
in TLC in both the dihalomethyl and trihalomethyl
ketone syntheses. The results were also confirmed by
Scheme 2 Scale-up synthesis
In subsequent study, some related control
experiments were conducted. First, the reaction of
simple acetophenone 5 with NBS didn’t provide any
brominated product 3a or 4a under the standard
conditions of Table 2, confirming that enaminones
are uniquely applicable for such metal-free synthesis
of halogenated ketones (eq 1). In addition,
performing the reaction in the presence of D2O (5
equiv) gave deuterium labelled product 3c-d1 together
with product 3c, suggesting that water participated
the reaction (eq 2). In addition, employing α-
bromoacetophenone
5
with NBS didn’t give
dibrominated product 3a, suggesting the 5 was not an
intermediate during the formation of 3 (Eq 3).
Analogously, the reaction of 3a with NBS didn’t
provided tribrominated product 4a, either (eq 4),
indicating against the formation of 3 during the
process generating products 4. In addition, in a
control experiment using Br2 as alternative bromine
source to react with 1a under the optimized
conditions in Table 1, no product 3a or 4a was
observed.
1
the H NMR analysis on the crude products given by
the model reactions synthesizing 3a and 4a,
respectively (see SI).
Based on these results given by control experiments,
the possible mechanism for this carbon-carbon bond
cleavage reaction is proposed. As outlined in Scheme
3, the reaction might start from the homo-cleavage of
BPO. The carboxyl radical generated thereby
incorporates to NXS to facilitate the formation of
halogen radical. This radical then adds to the C=C
double in enaminones to provide intermediate 6. The
coupling of 6 with carboxyl radical gives rise to 7
Scheme 1 Scope on the selective synthesis α,α,α-
tribromoaryl ketones
On basis of the synthetic scope investigation, the
scale-up experiments have also been executed. As
shown in Scheme 2, both the target products 3a and
3
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10.1002/adsc.201901234
Advanced Synthesis & Catalysis
was allowed to cool down to room temperature, and water
(10 mL) was added. The resulting suspension was
extracted with ethyl acetate (3×10 mL). The combined
organic phase was dried over anhydrous Na2SO4. After
filtration, the solution was employed rotating evaporator to
remove the solvent. The residue acquired therein was
subjected to silica gel column chromatography to provide
pure product with the elution of mixed petroleum ether and
ethyl acetate (v/v = 200 : 1).
which undergoes the elimination to afford
halogenated enaminone 8 and releases benzoic acid
(observed by GC, see SI). By repeating the free
radical addition process, the dihalogenated
intermediate 9 is generated. The single electron
transfer (SET) from 9 to the carboxyl radical yields
cation intermediate 10. The reaction of 10 with water
then leads to the intermediate 11. The subsequent
dissociation of the C-C bond in 11 affords the
dihalgoenated product 3 via proton transfer-based
decomposition by losing DMF (observed by GC, see
SI). On the other hand, when additional NBS is used,
the hemolysis of the bromine radical forms elemental
bromine in situ. The electrophilic substitution of the
cationic Br to the proton in 11 offers intermediate 12.
The transfer of bromine cation to the ketone α-site, as
well as the concurrent release of DMF from this
intermediate then yield tribrominated product 4.
2,2-Dibromo-1-phenylethan-1-one (3a).[6a] Yield 77%,
1
63.5 mg; yellow liquid; H NMR (400 MHz, CDCl3): δ
8.09 (d, J = 7.6 Hz, 2 H), 7.64 (t, J = 7.4 Hz, 1 H), 7.51 (t,
J = 7.8 Hz, 2 H), 6.71 (s, 1 H); 13C NMR (100 MHz,
CDCl3): 186.0, 134.4, 130.9, 129.7, 128.9, 39.7.
2,2-Dichloro-1-phenylethan-1-one (3b).[6d] Yield 80%,
1
45.2 mg; colorless liquid; H NMR (400 MHz, CDCl3): δ
8.09 (d, J = 8.4 Hz, 2 H), 7.66 (t, J = 3.6 Hz, 1 H), 7.52 (t,
J = 7.8 Hz, 2 H), 6.69 (s, 1 H); 13C NMR (100 MHz,
CDCl3): 185.9, 134.6, 131.4, 129.8, 128.9, 67.8.
2,2-Dibromo-1-(p-tolyl)ethan-1-one (3c).[6a] Yield 75%,
o
1
65.0 mg; yellow solid; mp 88-89 C; H NMR (400 MHz,
CDCl3): δ 7.98 (d, J = 8.0 Hz, 2 H), 7.30 (d, J = 7.6 Hz, 2
H), 6.70 (s, 1 H), 2.44 (s, 3 H); 13C NMR (100 MHz,
CDCl3): 185.6, 145.7, 129.8, 129.7, 128.3, 39.9, 21.8.
2,2-Dichloro-1-(p-tolyl)ethan-1-one (3d).[6d] Yield 77%,
o
1
46.6 mg; white solid; mp 49-50 C; H NMR (400 MHz,
CDCl3): δ 7.98 (d, J = 8.4 Hz, 2 H), 7.32 (d, J = 8.0 Hz, 2
H), 6.68 (s, 1 H), 2.44 (s, 3 H); 13C NMR (100 MHz,
CDCl3): 185.6, 145.9, 129.9, 129.7, 128.8, 67.8, 21.9.
2,2-Dibromo-1-(4-methoxyphenyl)ethan-1-one (3e).[6a]
o
1
Yield 78%, mg; white solid; mp 91-92 C; H NMR (400
MHz, CDCl3): δ 8.08 (d, J = 8.8 Hz, 2 H), 6.97 (d, J = 8.8
Hz, 2 H), 6.67 (s, 1 H), 3.90 (s, 3 H); 13C NMR (100 MHz,
CDCl3): 184.7, 164.6, 132.2, 123.4, 114.2, 55.7, 39.9.
2,2-Dibromo-1-(4-chlorophenyl)ethan-1-one
(3f).[6a]
1
o
Yield 78%, 71.8 mg; white solid; mp 91-92 C; H NMR
(400 MHz, CDCl3): δ 8.05 (d, J = 8.8 Hz, 2 H), 7.49 (d, J =
8.8 Hz, 2 H), 6.61 (s, 1 H); 13C NMR (100 MHz, CDCl3):
184.9, 141.1, 131.2, 129.3, 129.1, 39.2.
Scheme 3 The proposed reaction mechanism
2,2-Dichloro-1-(4-chlorophenyl)ethan-1-one
(3g).[6d]
1
o
Yield 70%, 46.3 mg; white solid; mp 59-60 C; H NMR
(400 MHz, CDCl3): δ 8.05 (d, J = 8.4 Hz, 2 H), 7.50 (d, J =
8.4 Hz, 2 H), 6.60 (s, 1H); 13C NMR (100 MHz, CDCl3):
184.9, 141.2, 131.2, 129.5, 129.3, 67.8.
Conclusion
In conclusion, we have disclosed a new free radical
C=C bond cleavage protocol for the synthesis of α,α-
dihalomethyl ketones and α,α,α-trihalomethyl ketones
without employing any metal reagent. The selectivity
in providing α,α-dihalogenated and α,α,α-
trihalogenated products can be easily controlled by
modifying the loading of halogen source and reaction
medium. Besides the tunable reaction selectivity, the
metal-free operation, mild reaction conditions as well
as broad scope constitute also the unique advantages
of the present synthetic methods.
2,2-Dibromo-1-(4-bromophenyl)ethan-1-one
(3h).[6a]
1
o
Yield 74%, 78.6 mg; white solid; mp 77-78 C; H NMR
(400 MHz, CDCl3): δ 7.98 (d, J = 8.8 Hz, 2 H), 7.66 (d, J =
8.4 Hz, 2 H), 6.60 (s, 1 H); 13C NMR (100 MHz, CDCl3):
185.1, 132.3, 131.2, 129.9, 129.6, 39.2.
1-(4-Bromophenyl)-2,2-dichloroethan-1-one
(3i).[6d]
1
o
Yield 71%, 56.7 mg; colorless solid; mp 48-49 C; H
NMR (400 MHz, CDCl3): δ 7.97 (d, J = 8.8 Hz, 2 H), 7.67
(d, J = 8.4 Hz, 2 H), 6.56 (s, 1 H); 13C NMR (100 MHz,
CDCl3): 185.2, 132.3, 131.3, 130.1, 129.9, 67.8.
2,2-Dibromo-1-(4-nitrophenyl)ethan-1-one (3j).[6f] Yield
o
1
74%, 71.0 mg; yellow solid; mp 58-59 C; H NMR (400
MHz, CDCl3): δ 8.37-8.35 (m, 2 H), 8.32-8.30 (m, 2 H),
6.61 (s, 1 H); 13C NMR (100 MHz, CDCl3): 184.5, 150.8,
135.6, 131.0, 124.0, 38.8.
Experimental Section
General procedure for the synthesis of α,α-
dihalomethyl ketones 3
2,2-Dibromo-1-(o-tolyl)ethan-1-one (3k).[6f] Yield 64%,
1
55.8 mg; yellow liquid; H NMR (400 MHz, CDCl3): δ
In a 25 mL round bottom flask equipped with stirring bar
and condenser were charged with enaminone 1 (0.3 mmol),
NXS 2 (X = Br and Cl, 0.6 mmol), BPO (0.15 mmol) and
p-xylene (2 mL). The resulting mixture was stirred at 60 oC
for 12 h under air atmosphere. Upon completion, the vessel
7.68 (d, J = 8.8 Hz, 1 H), 7.46 (t, J = 7.6 Hz, 1 H), 7.33-
7.29 (m, 2 H), 6.68 (s, 1 H) 2.51 (s, 3 H); 13C NMR (100
MHz, CDCl3): 188.6, 140.2, 132.7, 132.3, 128.1, 125.8,
125.1, 42.2, 21.1.
4
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10.1002/adsc.201901234
Advanced Synthesis & Catalysis
2,2-Dibromo-1-(2-bromophenyl)ethan-1-one (3l). Yield
71%, 75.3 mg; brown liquid; 1H NMR (400 MHz, CDCl3):
δ 7.64 (d, J = 7.6 Hz, 1 H), 7.57-7.55 (m, 1 H), 7.45 -7.37
(m, 2 H), 6.73 (s, 1 H); 13C NMR (100 MHz, CDCl3):
189.3, 136.5, 132.8, 130.8, 127.6, 119.1, 41.7; HRMS
(APCI) m/z cacld. for C8H5Br3O [M-H]-: 352.7818, found:
352.7813.
2,2-Dibromo-1-(furan-2-yl)ethan-1-one (3v).[6a] Yield
76%, 60.5 mg; brown liquid; 1H NMR (400 MHz, CDCl3):
δ 7.70 (d, J = 0.8 Hz, 1 H), 7.51 (d, J = 8.0 Hz, 1 H), 6.66
(dd, J1 = 3.6 Hz, J2 = 1.6 Hz, 1 H), 6.60 (s, 1 H); 13C NMR
(100 MHz, CDCl3): 175.4, 147.9, 146.9, 121.3, 113.3, 38.1.
2,2-dibromo-1-(pyridin-2-yl)ethan-1-one (3w).[6f] Yield
75%, 62.1 mg; yellow liquid; 1H NMR (400 MHz, CDCl3):
δ 8.70 (d, J = 8.0 Hz, 1 H), 8.19 (d, J = 7.6 Hz, 1 H), 7.90
(t, J = 7.8Hz, 1 H), 7.64 (s, 1 H), 7.58-7.55 (m, 1 H); 13C
NMR (100 MHz, CDCl3): 187.0, 149.3, 148.9, 137.6,
128.4, 124.2, 39.5.
1-(2-Bromophenyl)-2,2-dichloroethan-1-one (3m). Yield
64%, 51.0 mg; yellow liquid; 1H NMR (400 MHz, CDCl3):
δ 7.66 (dd, J1 = 7.6 Hz, J2 = 0.4 Hz, 1 H), 7.56 (dd, J1 = 7.2
Hz, J2 = 2.0 Hz, 1 H), 7.46-7.38 (m, 22 H), 6.75 (s, 1 H);
13C NMR (100 MHz, CDCl3): 189.4, 136.7, 133.7, 132.9,
130.4, 127.6, 119.3, 68.9; HRMS (APCI) m/z cacld. for
C8H5BrCl2O [M-H]-: 264.8828, found: 264.8823.
General procedure for the synthesis of α,α,α-
2,2-Dibromo-1-(2-nitrophenyl)ethan-1-one (3n). Yield
trihalomethyl ketones 4
o
1
68%, 65.5 mg; yellow solid; mp 43-44 C; H NMR (400
MHz, CDCl3): δ 8.96 (d, J = 1.8 Hz, 1 H), 8.51-8.47 (m, 2
H), 7.76 (d, J = 7.8 Hz, 1 H), 6.63 (s, 1 H); 13C NMR (100
MHz, CDCl3): 184.0, 148.4, 135.4, 132.2, 130.2, 128.5,
124.7, 38.6; HRMS (APCI) m/z cacld. for C8H5Br2NO3
[M-H]-: 319.8563, found: 319.8558.
In a 25 mL round bottom flask equipped with stirring bar
and condenser were charged with enaminone 1 (0.3 mmol),
NBS (0.9 mmol), BPO (0.15 mmol) and toluene (2 mL).
o
The resulting mixture was stirred at 60 C for 12 h under
air atmosphere. Upon completion, the vessel was allowed
to cool down to room temperature, and water (10 mL) was
added. The resulting suspension was extracted with ethyl
acetate (3×10 mL). The combined organic phase was dried
over anhydrous Na2SO4. After filtration, the solution was
employed rotating evaporator to remove the solvent. The
residue acquired therein was subjected to mixed petroleum
ether and ethyl acetate (v/v = 200 : 1) to provide pure
product.
2,2-Dibromo-1-(3-chlorophenyl)ethan-1-one (3o). Yield
78%, 79.1 mg; yellow liquid; 1H NMR (400 MHz, CDCl3):
δ 8.06 (d, J = 1.2 Hz, 1 H), 7.98 (d, J = 7.6 Hz, 1 H), 7.62-
7.60 (m, 1 H), 7.46 (t, J = 8.0 Hz, 1 H), 6.64 (s, 1 H); 13C
NMR (100 MHz, CDCl3): 184.8, 135.3, 134.4, 132.4,
130.2, 129.8, 127.8, 39.1; HRMS (APCI) m/z cacld. for
C8H5Br2ClO [M-H]-: 308.8323, found: 308.8320.
2,2,2-Tribromo-1-phenylethan-1-one (4a).[12] Yield 66%,
2,2-Dichloro-1-(3-chlorophenyl)ethan-1-one (3p). Yield
73%, 48.5 mg; colorless liquid; 1H NMR (400 MHz,
CDCl3): δ 8.07 (s, 1 H), 7.99 (d, J = 7.6 Hz, 1 H), 7.63 (dd,
J1 = 8.0 Hz, J2 = 0.4 Hz, 1 H), 7.48 (t, J = 8.0 Hz, 1 H),
6.61 (s, 1 H); 13C NMR (100 MHz, CDCl3): 184.9, 135.3,
134.5, 132.8, 130.2, 129.8, 127.8, 67.8; HRMS (APCI) m/z
cacld. for C8H5Cl3O [M-H]-: 220.9333, found: 220.9328.
1
70.1 mg; colorless liquid; H NMR (400 MHz, CDCl3): δ
8.34 (d, J = 8.0 Hz, 2 H), 7.61 (t, J = 7.4 Hz, 1 H), 7.48 (d,
J = 8.0 Hz, 2 H); 13C NMR (100 MHz, CDCl3): 181.2,
134.0, 131.8, 128.4, 128.3, 42.0.
2,2,2-Tribromo-1-(p-tolyl)ethan-1-one (4b).[12] Yield
70%, 77.3 mg; yellow liquid; 1H NMR (400 MHz, CDCl3):
δ 8.25 (d, J = 8.0 Hz, 2 H), 7.28 (d, J = 8.0 Hz, 2 H), 2.45
(s, 3 H); 13C NMR (100 MHz, CDCl3): 181.2, 145.2, 132.1,
129.0, 125.4, 42.5, 21.8.
2,2-Dichloro-1-(m-tolyl)ethan-1-one (3q).[6d] Yield 61%,
1
37.0 mg; yellow liquid; H NMR (400 MHz, CDCl3): δ
7.87 (d, J = 6.8 Hz, 2 H), 7.47 (d, J = 7.6 Hz, 1 H), 7.41 (d,
J = 8.0 Hz, 1 H), 6.70 (s, 1 H), 2.44 (s, 3 H); 13C NMR
(100 MHz, CDCl3): 186.1, 139.0, 135.4, 131.5, 130.2,
128.8, 126.9, 67.8, 21.4.
2,2,2-Tribromo-1-(4-methoxyphenyl)ethan-1-one (4c).[12]
o
1
Yield 68%, 78.0 mg; colorless solid; mp 38-39 C; H
NMR (400 MHz, CDCl3): δ 8.28 (d, J = 8.8 Hz, 2 H), 6.86
(d, J = 9.2 Hz, 2 H), 3.82 (s, 3 H); 13C NMR (100 MHz,
CDCl3): 180.1, 164.1, 134.6, 120.1, 113.6, 55.7, 42.8.
2,2-Dibromo-1-(3,4-dichlorophenyl)ethan-1-one
(3r).
o
1
Yield 58%, 59.7 mg; yellow solid; mp 66-67 C; H NMR
(400 MHz, CDCl3): δ 8.20 (d, J = 2.0 Hz, 1 H), 7.95 (dd, J1
= 8.4 Hz, J2 = 2.0 Hz, 1 H), 7.60 (d, J = 4.8 Hz, 1 H), 6.55
(s, 1 H); 13C NMR (100 MHz, CDCl3): 184.0, 139.3, 133.8,
131.7, 131.0, 130.3, 128.8, 38.7; HRMS (APCI) m/z cacld.
for C8H4Br2Cl2O [M-H]-: 342.7933, found: 342.7932.
2,2,2-Tribromo-1-(4-fluorophenyl)ethan-1-one (4d).[12]
1
Yield 68%, 76.0 mg; colorless oil; H NMR (400 MHz,
CDCl3): δ 8.42-8.39 (m, 2 H), 7.16 (t, J = 8.0 Hz, 2 H); 13C
NMR (100 MHz, CDCl3): 180.1, 166.0 (d, J = 256.8 Hz),
134.8 (d, J = 9.6 Hz), 124.4, 115.6 (d, J = 21.9 Hz), 41.5.
1-(Benzo[d][1,3]dioxol-5-yl)-2,2-dibromoethan-1-one
o
1
(3s).[6a] Yield 75%, 72.1 mg; white solid; mp 94-95 C; H
NMR (400 MHz, CDCl3): δ 7.70 (dd, J1 = 8.0 Hz, J2 = 1.6
Hz, 1 H), 7.54 (d, J = 1.6 Hz, 1 H), 6.89 (d, J = 8.4 Hz, 1
H), 6.65 (s, 1 H), 6.09 (s, 2 H); 13C NMR (100 MHz,
CDCl3): 184.4, 153.0, 148.5, 126.4, 125.1, 109.4, 108.3,
102.3, 39.6.
2,2,2-Tribromo-1-(4-chlorophenyl)ethan-1-one (4e).[12]
1
Yield 72%, 83.5 mg; brown liquid; H NMR (400 MHz,
CDCl3): δ 8.29 (d, J = 8.8 Hz, 2 H), 7.46 (d, J = 8.4 Hz, 2
H); 13C NMR (100 MHz, CDCl3): 180.5, 140.6, 133.3,
128.7, 126.6, 41.3.
2,2,2-Tribromo-1-(4-bromophenyl)ethan-1-one (4f).[12]
2,2-Dibromo-1-(naphthalen-2-yl)ethan-1-one
(3t).[6a]
1
1
o
Yield 71%, 92.1 mg; brown liquid; H NMR (400 MHz,
Yield 66%, 64.3 mg; yellow solid; mp 87-88 C; H NMR
(400 MHz, CDCl3): δ 8.63 (s, 1 H), 8.08 (dd, J1 = 8.8 Hz,
J2 = 1.2 Hz, 1 H), 7.99 (d, J = 8.0 Hz, 1 H), 7.94-7.89 (m, 2
H), 7.65 (t, J = 7.4 Hz, 1 H), 7.59 (t, J = 7.4 Hz, 1 H), 6.87
(s, 1 H); 13C NMR (100 MHz, CDCl3): 186.0, 136.1, 132.3,
CDCl3): δ 8.21 (d, J = 8.8 Hz, 2 H), 7.62 (d, J = 8.8 Hz, 2
H); 13C NMR (100 MHz, CDCl3): 180.7, 133.3, 131.7,
129.5, 127.0, 41.2.
131.8, 129.9, 129.5, 128.9, 128.1, 127.9, 127.3, 124.7, 39.8. 2,2,2-Tribromo-1-(o-tolyl)ethan-1-one (4g).[12] Yield
62%, 68.5 mg; colorless liquid; 1H NMR (400 MHz,
2,2-Dibromo-1-(thiophen-3-yl)ethan-1-one (3u).[6a] Yield
CDCl3): δ 8.01 (d, J = 8.0 Hz, 1 H), 7.41 (t, J = 7.6 Hz, 1
H), 7.31 (d, J = 7.6 Hz, 1 H), 7.24 (t, J = 8.0 Hz, 1 H), 2.40
(s, 3 H); 13C NMR (100 MHz, CDCl3): 187.5, 137.9,
132.4,131.3, 131.2, 128.3, 125.1, 43.7, 20.8.
o
1
60%, 50.8 mg; brown solid; mp 50-51 C; H NMR (400
MHz, CDCl3): δ 8.38 (d, J = 2.8 Hz, 1 H), 7.68 (d, J = 5.2
Hz, 1 H), 7.39-7.37 (m, 1 H), 6.42 (s, 1 H); 13C NMR (100
MHz, CDCl3): 180.5, 135.3, 134.6, 128.0, 126.8, 40.2.
5
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10.1002/adsc.201901234
Advanced Synthesis & Catalysis
2,2,2-Tribromo-1-(m-tolyl)ethan-1-one (4h).[12] Yield
68%, 75.2 mg; yellow liquid; 1H NMR (400 MHz, CDCl3):
δ 8.16 (d, J = 7.6 Hz, 1 H), 8.10 (s, 1 H), 7.42 (d, J = 7.6
Hz, 1 H), 7.36 (t, J = 7.8 Hz, 1 H), 2.44 (s, 3 H); 13C NMR
(100 MHz, CDCl3): 181.9, 138.2, 134.8, 132.3, 129.0,
128.4, 128.0, 42.3, 21.5.
Kumar, Synlett 2012, 1013. (c) R. Pundeer, V. Kiran, R.
Prakash, Sushma, S. C. Bhatia, C. Sharma, K. R. Aneja,
Med. Chem. Res. 2012, 21, 4043.
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Casper, J. Org. Chem. 1971, 36, 88. (b) K. R. Henery-
Logan, T. L. Fridinger, Chem. Commun. 1968, 130. (c)
K. Kędziora, F. R. Bisogno, I. Lavandera, V. Gotor-
Fernández, J. Montejo-Bernardo, S. García-Granda, W.
Kroutil, V. Gotor, ChemCatChem 2014, 6, 1066.
2,2,2-Tribromo-1-(3-methoxyphenyl)ethan-1-one (4i).
1
Yield 58%, 66.8 mg; yellow liquid; H NMR (400 MHz,
CDCl3): δ 7.96 (d, J = 7.6 Hz, 1 H), 7.81 (s, 1 H), 7.38 (t, J
= 8.0 Hz, 1 H), 7.15 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz 1 H),
3.87 (s, 3 H); 13C NMR (100 MHz, CDCl3): 181.5, 159.2,
130.2, 129.2, 124.3, 120.3, 116.6, 55.5, 41.9; EI-HRMS
m/z cacld. for C9H7Br3O2 [M]+: 383.7996, found: 383.8007.
[4] (a) M. S. Perryman, M. E. Harris, J. L. Foster, A. Joshi,
G. J. Clarkson, D. J. Fox, Chem. Commun. 2013, 49,
10022. (b) Y. Aoki, K. Oshima, K. Utimoto, Synlett
1995, 1071. (c) R. N. Ram, V. K. Soni, D. K. Gupta,
Tetrahedron 2012, 68, 9068. (d) R. Díaz-Hernández, I.
Zaragoza-Galicia, H. F. Olivo, M. Romero-Ortega,
ChemistrySelect 2017, 2, 10067. (e) A. Jayaraman, E.
Cho, F. M. Irudayanathan, J. Kin, S. Lee, Adv. Synth.
Catal. 2018, 360, 130. (f) B. Jiang, Y. Feng, J.-F.
Huang, Tetrahedron: Asymmetry 2001, 12, 2323.
2,2,2-Tribromo-1-(3-chlorophenyl)ethan-1-one (4j).[12]
1
Yield 63%, 73.1 mg; yellow liquid; H NMR (400 MHz,
CDCl3): δ 8.28 (s, 1 H), 8.23 (d, J = 6.8 Hz, 1 H), 7.58 (dd,
J1 = 8.0 Hz, J2 = 0.8 Hz 1 H), 7.43 (t, J = 8.0 Hz, 1 H); 13C
NMR (100 MHz, CDCl3): 180.5, 134.5, 133.9, 131.7,
130.1, 129.8, 129.5, 40.1.
1-(Benzo[d][1,3]dioxol-5-yl)-2,2,2-tribromoethan-1-one
(4k).[12] Yield 63%, 75.0 mg; yellow liquid; 1H NMR (400
MHz, CDCl3): δ 8.04 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz 1 H),
7.80 (d, J = 2.0 Hz, 1 H), 6.88 (d, J = 6.8 Hz, 1 H), 6.09 (s,
2 H); 13C NMR (100 MHz, CDCl3): 179.8, 152.6, 147.6,
129.1, 121.7, 111.7, 107.9, 102.3, 42.3.
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Dorsky, Org. Synth. 1943, 23, 48. (b) S. G. Cohen, H.
T. Wolosinski, P. J. Scheuer, J. Am. Chem. Soc. 1950,
72, 3952. (c) J. Kagan, S. K. Arora, M. Bryzgis, S. N.
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9814. (f) K. Kawakami, A. Tsuda, Chem. Asian J. 2012,
7, 2240.
2,2,2-Tribromo-1-(furan-2-yl)ethan-1-one (4l). Yield
55%, 56.9 mg; yellow liquid; 1H NMR (400 MHz, CDCl3):
δ 7.71 (s, 1 H), 7.69 (d, J = 3.6 Hz, 1 H), 6.64 (d, J = 2.8
Hz, 1 H); 13C NMR (100 MHz, CDCl3): 170.7, 148.2,
144.0, 124.2, 112.7, 39.5; EI-HRMS m/z cacld. for
C6H3Br3O2 [M]+: 343.7683, found: 343.7696.
2,2,2-Tribromo-1-(thiophen-2-yl)ethan-1-one
(4m).
1
Yield 60%, 65.0 mg; yellow liquid; H NMR (400 MHz,
CDCl3): δ 8.28 (d, J = 4.0 Hz, 1 H), 7.75 (d, J = 4.8 Hz, 1
H), 7.18 (t, J = 4.4 Hz, 1 H); 13C NMR (100 MHz, CDCl3):
175.5, 137.4, 136.5, 132.7, 128.2, 40.9; EI-HRMS m/z
cacld. for C6H3Br3OS [M]+: 359.7455, found: 359.7453.
[6] (a) C. Wu, X. Xin, Z.-M. Fu, L.-Y. Xie, K.-J. Liu, Z.
Wang, W. Li, Z.-H. Yuan, W.-M. He, Green Chem.
2017, 19, 1983. (b) J. Liu, W. Li, C. Wang, Y. Li, Z. Li,
Tetrahedron Lett. 2011, 52, 4320. (c) V. Conte, B.
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2,2,2-Tribromo-1-(thiophen-3-yl)ethan-1-one
(4n).
1
Yield 63%, 67.8 mg; yellow liquid; H NMR (400 MHz,
CDCl3): δ 8.58 (d, J = 2.8 Hz, 1 H), 7.84 (d, J = 4.4 Hz, 1
H), 7.35-7.33 (m, 1 H); 13C NMR (100 MHz, CDCl3):
176.0, 137.6, 130.5, 130.1, 125.7, 42.7; EI-HRMS m/z
cacld. for C6H3Br3OS [M]+: 359.7455, found: 359.7469.
[7] (a) M. A. Romero-Reyes, I. Zaragoza-Calicia, H. F.
Olivo, M. Romero-Ortega, J. Org. Chem. 2016, 81,
9515. (b) T. Imanishi, Y. Fujiwara, Y. Sawama, Y.
Monguchi, H. Sajiki, Adv. Synth. Catal. 2012, 354, 771.
Acknowledgements
This work is financially supported by National Natural Science
Foundation of China (no. 21562025) and Education Department
of Jiangxi Province (GJJ170213).
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10.1002/adsc.201901234
Advanced Synthesis & Catalysis
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7
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Advanced Synthesis & Catalysis
FULL PAPER
Switchable Synthesis of α,α-Dihalomethyl and
α,α,α-Trihalomethyl Ketones by Metal-Free
Decomposition of Enaminone C=C Double Bond
Adv. Synth. Catal. Year, Volume, Page – Page
Yunyun Liu*, Jin Xiong, Li Wei, Jie-Ping Wan*
8
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