Bromination of α-Diazo Phenylacetate Derivatives Using Cobalt(II) Bromide

Article abstract of DOI:10.1002/adsc.202000009

A method for the bromination of α-diazo phenylacetate derivatives using cobalt(II) bromide is described. This bromination reaction features a short reaction time, broad substrate scope, operational simplicity, acid-free conditions, and gram-scalability. (Figure presented.).

Full text of DOI:10.1002/adsc.202000009

Title: Bromination of α-Diazo Phenylacetate Derivatives using CoBr2
Authors: Haifeng Wang, Xiangli Sun, Manman Hu, Xiaoyi Zhang, Lele
Xie, and Shuang-Xi Gu
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10.1002/adsc.202000009
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Bromination of α-Diazo Phenylacetate Derivatives Using
Cobalt(II) Bromide
Haifeng Wang a*, b, Xiangli Sun a, b, Manman Hu b, Xiaoyi Zhang b, Lele Xie b, Shuangxi
Gu a *
a School of Chemical Engineering & Pharmacy, Wuhan Institute of Technology, Wuhan 430205, P. R. of China
b School of Chemistry & Chemical Engineering, Zhoukou Normal University, Zhoukou, 466001, Henan, P. R. of China
E-mail address: skytacle@139.com (H. Wang); shuangxigu@163.com (S. Gu)
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######.((Please
delete if not appropriate))
bromine or hydrogen bromide (Scheme 2a).[4] While
Abstract. A method for the bromination of α-diazo
phenylacetate derivatives using cobalt(II) bromide is this approach facilitates the replacement of a diazo
described. This bromination reaction features a short
reaction time, broad substrate scope, operational simplicity,
acid-free conditions, and gram-scalability.
group by a readily available, highly specific
brominating reagent, the reaction is generally
conducted under harsh conditions. Additionally,
secondary precautions are required to ensure safe
handling as bromine is a hazardous irritant that causes
painful skin blisters and severe respiratory damage.
Hydrogen bromide has limited applicability due to its
strong acidity and long reaction time. Therefore,
continued efforts should be dedicated to investigating
new routes and reagents for the synthesis of
brominated α-phenylacetate derivatives.
Keywords: bromination; α-diazo phenylacetate
derivatives; cobalt(II) bromide; cobalt-mediated; bromides
As electrophiles in a wide variety of reactions,
bromides can be converted through simple
transformations to generate various valuable synthetic
intermediates and significant products (Scheme 1).[1]
Many methodologies for the construction of
carbon−bromine bonds have been reported.[2] Among
them, the bromination of diazo compounds is an
especially practical and useful strategy.[3] However, to
the best of our knowledge, very few studies have been
designed to achieve the bromination of α-diazo
phenylacetate derivatives. To date, traditional
synthetic routes for this transformation use elemental
Scheme 2. Previous work and our current strategy
Cobalt bromide salts are versatile reagents in many
organic reactions,[5] which can be used to mediate the
bromination of the diazo compounds. Thus, they are
attractive alternatives for the synthesis of α-
brominated phenylacetate derivatives without the use
of any acid (Scheme 2b). In our study, the initial
optimization of the bromination of donor−acceptor
diazo compounds was conducted using ethyl 2-diazo-
2-phenylacetate as the model substrate to react with
various metal bromides.
Scheme 1. Various routes of synthesis using bromides as
intermediates
1
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10.1002/adsc.202000009
Advanced Synthesis & Catalysis
Raising the reaction temperature enhanced the yield
dramatically (Entry 12), whereas decreasing the
reaction temperature led to lower yields. No further
improvement of the product yield was noted when the
Table 1. Optimization of the reaction conditions
Table 2. Reaction scope a
Entry Brominating
agents
Solvent
Yield g) (%)
1
NiBr2
CuBr2
CuBr
FeBr3
THF
N.R.
21
8
2
THF
3
THF
4
THF
47
71
63
67
56
46
70
78
89
67
86
63
58
.
5
CoBr2 6H2O
THF
.
6
CoBr2 6H2O
CH3CN
EtOH
.
7
CoBr2 6H2O
.
8
CoBr2 6H2O
DMF
.
9
CoBr2 6H2O
DMSO
.
10
11
12b)
13c)
14d)
15e)
CoBr2 6H2O
toluene
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
.
CoBr2 6H2O
.
CoBr2 6H2O
.
CoBr2 6H2O
.
CoBr2 6H2O
.
CoBr2 6H2O
16 f)
CoBr2 6H2O
.
a)
Unless otherwise noted, all reactions were conducted
with ethyl 2-diazo-2-phenylacetate (0.5 mmol) and
.
b)
CoBr2 6H2O (0.3 mmol) at 80 °C under N2 atmosphere.
c)
The reaction temperature was 100 °C.
The reaction
d)
temperature was 70 °C. The amount of the brominating
reagent was 0.4 mmol. e) The amount of the brominating
reagent was 0.2 mmol. The reaction proceeded in air. g)
f)
Yield of the isolated product.
The effects of various promoters, metal salts,
solvents, and temperatures were examined using a
model reaction (Table 1). Initially, four different
brominating reagents were screened (MBrn, M = Ni,
Cu, Fe, Co) (Entries 1−5). There was no reaction with
NiBr2, whereas CuBr2 and CuBr gave product 6a in
21% and 8% yields, respectively (Entries 1–3).
Similarly, FeBr3 resulted in the expected product 6a
in 47% yield (Entry 4). It is noteworthy that 6a was
.
obtained in 71% yield when 0.6 equiv. of CoBr2 6H2O
was used in THF at 80 °C for 1 h under N2
atmosphere (Entry 5). Several other solvents were
screened, and a lower or comparable yield was
obtained when acetonitrile (CH3CN), ethanol (EtOH),
N,N-dimethylformamide (DMF), dimethylsulfoxide
(DMSO), or toluene were used as the solvent (Table
1, Entries 6−10). The highest product yields were
observed when 1,4-dioxane was used as the solvent
(Entry 11). Encouraged by this initial result, we
focused on optimizing other reaction parameters.
a)
Unless otherwise noted, all reactions were conducted
with ethyl 2-diazo-2-phenylacetate (0.5 mmol) and
CoBr2 6H2O (0.3 mmol) at 100 °C under N2 atmosphere.
.
2
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10.1002/adsc.202000009
Advanced Synthesis & Catalysis
reaction time was extended (Table 1, Entry 13). The thiophene ring was also compatible, affording the
yield of 6a was not further improved when the desired product in 80% yield (6ab). Alkyl substrates
amount of the brominating reagent was increased to were also examined, but no desired product was
0.4 mmol (Table 1, Entry 14). Lowering the amount obtained (see Supporting Information).
.
of CoBr2 6H2O diminished the yield of this
transformation drastically (Table 1, Entry 15). A
The synthetic potential of this process was
demonstrated by conducting a gram-scale reaction of
.
.
negative control experiment with CoBr2 6H2O/air
ethyl 2-diazo-2-phenylacetate and CoBr2 6H2O,
highlighted the critical role played by the N2
atmosphere (Entry 16). In air atmosphere, 5a tends to
undergo an oxidation reaction which gives an
oxidized byproduct. That is a common side reaction
observed in metal carbene chemistry.[6] Attempting to
reduce the amount of cobalt salt and use inexpensive
KBr as bromine source, various bromine-free cobalt
salts as catalysts were tested in the bromination
reaction. However, no desired product was afforded,
whereas a low yield (8%) of 6a was obtained when
thereby affording 6a in 82% yield (Scheme 3a).
Treatment of 6a with morpholine in the presence of
Et3N at room temperature resulted in the formation of
the amination product 8 in 80% yield (Scheme 3b).
Substitution
of
the
bromide
using
2-
mercaptobenzothiazole gave the corresponding
thioether 9 in 73% yield. The cyclization reaction was
performed at 110 °C with benzothioamide and
proceeded smoothly to deliver compound 10 in 55%
yield.[7]
.
only using a catalytic amount of CoBr2 6H2O (see
Supporting Information). Thus, after careful
investigation, the optimized reaction conditions were
.
identified as CoBr2 6H2O (0.3 mmol) in 1,4-dioxane
at 100 °C under N2 atmosphere for 1 h.
With the optimized reaction conditions in hand, we
then undertook an extensive survey of the substrate
scope. Diverse α-diazo phenylacetate derivatives 5a−
.
5ab were reacted with CoBr2 6H2O to give the desired
products in good to excellent yields under the
optimized reaction conditions (Table 2).
Generally, we found that ester moieties bearing
linear, branched, bulky, and saturated alkoxy chains
were well tolerated as the corresponding products
were obtained in good yields (6a–e). A substrate
bearing a lactone also gave the desired product in
high yields (6aa). We observed that unsaturated
alkoxy chains had little influence on this reaction,
giving the desired product 6f in 71% yield.
Satisfactory results were obtained when there were
methyl, tert-butyl, or methoxy groups on the phenyl
moiety of the diazoacetate as good yields were
obtained in short reaction time; this trend was
possibly due to the presence of the electron-donating
substituents, which increased the overall reactivity of
the diazoacetate (6g, 6i–k). This explanation was
supported by the high yield obtained in 30 min for the
3,5-dimethoxy group on the bis-substituted substrate
6h. In contrast, although strongly electron-
withdrawing functional groups had no adverse effect
on the reaction yield (83%–93%), longer reaction
times were observed, presumably due to the relatively
low activity imparted by these substituents (6l–q).
Substrates bearing a halide substitution (F, Cl, Br, and
I) on the ortho, meta, or para positions of the aryl
group also gave the desired products in good to
excellent yields (6r–y). The reaction also proceeded
well with a 2-naphthyl group to give the product 6z in
85% yield. Furthermore, a substrate containing a
Scheme 3. Gram-scale synthesis and synthetic
transformations
Scheme 4. Control experiment
3
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10.1002/adsc.202000009
Advanced Synthesis & Catalysis
derivatives. More importantly, the synthetic potential
of this novel method is documented through a series
of valuable follow-up transformations. Further efforts
toward developing viable routes for the iodination and
chlorination of diazo compounds are currently
underway.
Further insight into the bromination reaction came
via the control experiments (Scheme 4). The reaction
products are rather complicated, and the formation of
a small amount of product 6a might be attributed to
the existence of trace amount of H2O (Eq. a). When
D2O was added to the reaction system, product 6a
was deuterated with a yield percentage of 91% based
1
on H NMR analysis (Eq. b). These results revealed
Experimental Section
that the crystal water of the cobalt bromide salts
participated in the proton shuttle process.
Additionally, the reaction proceeded smoothly in
basic conditions (Na2CO3 or Et3N), which indicated
General procedure for the bromination of α-diazo
phenylacetate derivatives
To
a
stirred solution of the respective α-diazo
that the transformation did not occur through the HBr phenylacetate derivative (0.5 mmol) in 1,4-dioxane (1 mL)
.
.
was added CoBr2 6H2O (0.3 mmol). The resulting solution
was stirred at 100 °C under N2 atmosphere. After
pathway from CoBr2 6H2O with heating (Eq. c).
completion, the resulting mixture was filtered, and the
solvent was removed under vacuum. The resulting crude
product was purified using column chromatography (silica
gel, petroleum ether/ethyl acetate = 40:1) to afford the
corresponding brominated α-phenylacetate derivative.
Building on the information gathered from the
control experiments, a plausible mechanism was
proposed (Scheme 5). Nowadays, cobalt carbenes are
important reaction intermediates or catalysts for many
organic reactions.[8] Typically, the process is initiated
by the generation of intermediate I in situ from the Acknowledgments
diazo ester 5a, leading to complete conversion to the
highly active cobalt carbenoid II via the loss of
The work is supported by the Key Scientific and
nitrogen under thermal conditions. Nucleophilic
attack of the carbocation of intermediate III by the
bromine atom gives intermediate IV. At the same
time, the proton from the crystal water is trapped to
afford the corresponding brominated α-phenylacetate
6a. The cobalt species 10 is released, which then
regenerates similar cobalt carbenes for the final
transformation step.
Technological Project of Henan Province (NO.
192102310409), the High-level Personal Fund of Zhoukou
Normal University (No. ZKNUC2017040), and the
National Natural Science Foundation of China (No.
21877087). The valuable suggestions from Prof. Quanrui
Wang of Fudan University and Prof. Xiuqin Dong of
Wuhan University are greatly appreciated.
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Scheme 5. Proposed reaction mechanism
In summary, we have developed a novel process for
the cobalt-mediated bromination of α-diazo
phenylacetate derivatives using cobalt (II) bromide.
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5
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10.1002/adsc.202000009
Advanced Synthesis & Catalysis
COMMUNICATION
Bromination of α-Diazo Phenylacetate Derivatives
using CoBr2
Adv. Synth. Catal. Year, Volume, Page–Page
Haifeng Wang a*, b, Xiangli Sun a, b, Manman Hu b,
Xiaoyi Zhang b, Lele Xie b, Shuangxi Gu a *
6
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