Practical bromination of arylhydroxylamines with SOBr2 towards ortho-bromo-anilides

Article abstract of DOI:10.1016/j.tetlet.2021.153074

A facile approach for synthesizing ortho-bromoanilides from readily available aryhydroxylamines and thionyl bromide is demonstrated in this work. Mild reaction conditions and broad scope of substrates ranging from heterocyclic structures to pharmaceutics-potential motifs are used in the reactions of this paper. Efficient bromination of ortho C–H bonds of the aryhydroxylamines has been achieved. Ortho-bromoanilide products were obtained in good to excellent yields, and model scaled-up reactions of this synthetic approach are shown in this work.

Full text of DOI:10.1016/j.tetlet.2021.153074

Tetrahedron Letters 72 (2021) 153074
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Practical bromination of arylhydroxylamines with SOBr2 towards
ortho-bromo-anilides
⇑
⇑
Yuanbo Du, Zhenguo Xi, Lirong Guo, Haifeng Lu , Lei Feng, Hongyin Gao
School of Chemistry and Chemical Engineering, Key Laboratory of Colloid and Interface Chemistry, Ministry of Education, Shandong University, Ji’nan 250100, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile approach for synthesizing ortho-bromoanilides from readily available aryhydroxylamines and
thionyl bromide is demonstrated in this work. Mild reaction conditions and broad scope of substrates
ranging from heterocyclic structures to pharmaceutics-potential motifs are used in the reactions of this
paper. Efficient bromination of ortho CAH bonds of the aryhydroxylamines has been achieved. Ortho-bro-
moanilide products were obtained in good to excellent yields, and model scaled-up reactions of this
synthetic approach are shown in this work.
Received 5 March 2021
Revised 4 April 2021
Accepted 7 April 2021
Available online 13 April 2021
Keywords:
Ó 2021 Elsevier Ltd. All rights reserved.
Arylhydroxylamines
Thionyl bromide
Bromination
Metal and oxidant free
Bromoanilides
Introduction
byproducts, for instance, the overbromination products and multi-
ple regioisomers. Transition metal-catalyzed directed regioselec-
Aryl halides are very valuable chemicals in modern organic
chemistry since their widespread applications in transition-metal
catalyzed cross-coupling reactions as key substrates to afford
diverse CAC, CAN, CAO and CAS bonds [1]. In addition, aryl halides
have also been widely used in transition-metal-free transforma-
tions, such as nucleophilic aromatic substitution [2], generation
of highly reactive organometallic reagents (e.g. aryllithium, aryl-
magnesium reagents) and benzyne species. Furthermore, aryl
halides serve as key components of a wide range of natural prod-
ucts [3], pharmaceuticals [4], as well as functional materials [5].
Among these aryl halides, halogenated anilines are particularly
attractive due to their frequent appearance in dyes and pigments
[6]. Since the aryl bromides have higher reactivity and represent
easier conversion to more desirable targets than the corresponding
aryl chloride, therefore the development of mild, efficient and
regioselective bromination of anilides is still highly desired.
Electrophilic aromatic substitution/bromination, employing
bromine [7], N-bromosuccinimides [8], peroxides/HBr [9] and
DMSO/HBr [10] as brominating reagents, is the dominant strategy
to aryl bromides (Scheme 1a). While powerful, these approaches
were suffering from several limitations: (1) the employment of
highly toxic or hazardous reagents; (2) only the activated arenes
were amenable to these protocols; (3) the formation of undesirable
tive CAH bromination was found to be an efficient approach to
ortho-brominated aromatic compounds [11]. Unfortunately these
transformations usually require the employment of expensive
metal catalysts, such as palladium, rhodium, and long-time heating
at high temperature for completion (Scheme 1b). Recently, a vari-
ety of Lewis basic organocatalysts were successfully applied to
the electrophilic bromination of aryl compounds that represents
a more environmentally friendly route than the metal catalyst sys-
tem [12]. However, these strategies often suffer from the specific
catalysts and the narrow substrate scope. Thus, it is still attractive
to develop a metal and oxidant free alternative protocol for the
rapid access to bromoarenes under mild conditions.
In 2006, Shi and co-workers elegantly reported a palladium-cat-
alyzed ortho-selective halogenation of acetanilides employing CuX2
(X = Cl, Br) as halogen source (Scheme 1c) [11a]. A milder palladium-
catalyzed orthoACAH halogenation of anilides with NXS (X = Cl, Br)
in the presence of p-toluenesulfonic acid (PTSA) was developed by
Bedford and co-workers in 2011 (Scheme 1c) [11f]. Recently, we
demonstrated that arylhydroxylamines can be O-alkenylated or O-
arylated with a series of electrophiles, and the transient intermedi-
ates can undergo a cascade [3,3]-sigmatropic rearrangement and re-
aromatization to afford structurally diverse indoles [13] or biaryl
products [14], respectively. As part of our continuous interest in
arylhydroxylamines, we are pleased to describe herein a transition
metal-free facile approach to ortho-bromoanilides by treatment of
⇑
Corresponding authors.
E-mail addresses: lhf@sdu.edu.cn (H. Lu), hygao@sdu.edu.cn (H. Gao).
https://doi.org/10.1016/j.tetlet.2021.153074
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

Y. Du, Z. Xi, L. Guo et al.
Tetrahedron Letters 72 (2021) 153074
9–14). Reducing the amount of base resulted in a slightly improve-
ment in yield from 69% to 74% (Table 1, entries 15 and 16). After
extensive screening of temperatures, we found that adding thionyl
bromide at 0 °C and then slowly warming it to room temperature
can improve the results (Table 1, entries 17–19). We were pleased
to find that the isolated yield of 2a can be increased up to 97% in
dichloromethane in the absence of base at 0 °C to room tempera-
ture for 1 h and only trace amount of 2a0 was detected (Table 1,
entry 20).
With the optimized reaction conditions in hand, we began to
examine the scope of this ortho-bromination protocol under stan-
dard conditions as shown in Table 2. A variety of protecting-group
onto the nitrogen atom of the 2-naphthyl hydroxylamine, such as
Bz-, Ac-, Piv-, -CO2Me, Cbz-, Fmoc-, TFA-, except for Boc, were
amenable to this transformation to furnish the corresponding
ortho-bromoanilides in good to excellent yields with excellent
regioselectivity (Table 2, entries 1–8). These results also revealed
that the benzoyl group was the optimal protecting-group of the
arylhydroxylamines (Table 2, entry 1). For substrates bearing
OMe, OBn, Br and aryl functional group on the naphthalene ring,
the desired products 2i-2q were obtained with high yields (Table 2,
entries 9–17). Furthermore, phenylhydroxylamines with various
substituents on the phenyl ring were next investigated, affording
the corresponding ortho-brominated products in moderate to high
yields and excellent regioselectivity under standard conditions
(Table 2, entries 18–32). Notably, substrates bearing electron-
withdrawing groups, such as Cl, Br, I, CF3, were tolerated albeit
with moderate yields, indicating the feasibility of this transforma-
tion with electron-deficient system (Table 2, entries 19–21, 24 and
32). When N-(3-fluorophenyl)-N-hydroxybenzamide 1ab was
tested, bromination occurred at the 6-position and 2-position of
benzene ring, and the ratio of regioisomers was 2 to 1. Its regiose-
lectivity might be due to the influence of steric and electronic
effect, and 2ab and 2ab0 could be separated by column chromatog-
raphy (Table 2, entry 28). Moreover, this method was tolerant of
Scheme 1. Synthetic routes to aryl bromides and ortho-bromoanilides.
arylhydroxylamines with thionyl bromide under mild conditions
(Scheme 1d).
Results and discussion
At the outset of investigation, the reaction between N-hydroxy-
N-(naphthalen-2-yl)benzamide 1a and thionyl bromide was exam-
ined in THF at ꢀ20 °C using Na2CO3 as base. We delightedly found
that the expected N-(1-bromonaphthalen-2-yl)benzamide 2a was
isolated in 31% yield and 60% of N-(naphthalen-2-yl)benzamide
2a0 was also isolated (Table 1, entry 1). In order to inhibit the unde-
sired side product 2a0, we screened various solvents (Table 1,
entries 2–8) and found that dichloromethane was the optimal
option (Table 1, entry 8). The influence of base was next investi-
gated, and revealed that the employment of different bases had
limited effect on the yield of the desirable product (Table 1, entries
Table 1
Optimization of the reaction conditions.a
entry
solvent
base
temp.
2a,yieldb
2a’,yieldb
1
2
3
4
5
6
7
8
THF
DCE
Et2O
CHCl3
CCl4
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
pyridine
Et3N
ꢀ20 °C
ꢀ20 °C
ꢀ20 °C
ꢀ20 °C
ꢀ20 °C
ꢀ20 °C
ꢀ20 °C
ꢀ20 °C
ꢀ20 °C
ꢀ20 °C
ꢀ20 °C
ꢀ20 °C
ꢀ20 °C
ꢀ20 °C
ꢀ20 °C
ꢀ20 °C
ꢀ10 °C
0 °C
31%
54%
42%
62%
9%
60%
23%
35%
16%
4%
EtOAc
PhCl
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
17%
49%
69%
34%
32%
58%
60%
57%
52%
72%
74%
72%
71%
83%
97%
51%
32%
20%
36%
20%
36%
28%
26%
14%
24%
20%
18%
20%
6%
9
10
11
12
13
14
15c
16d
17d
18d
19d
20
K2CO3
NaHCO3
K3PO4
DIPA
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
None
0 °C to r.t.
0 °C to r.t.
2%
a
b
c
Unless otherwise noted, all reactions were carried out under the following conditions: 1a (0.2 mmol), SOBr2 (1.2 eq.), base (2.0 eq.), solvent (1 mL), 1 h.
Yields of isolated products.
1.0 equivalents of base was employed.
d
0.5 equivalents of base was employed. DCE = 1,2-dichloroethane; DCM = Dichloromethane; DIPA = Diisopropylamine.
2

Y. Du, Z. Xi, L. Guo et al.
Tetrahedron Letters 72 (2021) 153074
Table 2
Substrate scope.a,b
.
aReaction conditions: 1 (0.2 mmol), SOBr2 (0.24 mmol), DCM (1 mL) at 0 °C to r.t. under N2 for 1 h. For substrates 2r-2al, 4 Å MS (100 mg) was employed as additive. bYields of
isolated products. cYield in the parenthesis is the isolated yield of N-phenylbenzamide. N-(4-bromophenyl)benzamide was not detected in this transformation. dThe
regioselectivity was determined by the ratio of isolated yield of 2ab and 2ab0. Combined yield of the pure regioisomers. Bz = benzoyl; Ac = Acetyl; Boc = t-Butyloxy carbonyl;
Cbz = benzoxycarbonyl; Piv = pivaloyl; Fmoc = 9-fluorenylmethyloxycarbonyl; TFA = Trifluoroacetyl; Bn = benzyl.
To further evaluate the compatibility of the current method is
not trivial compared with the literature reported protocols
[10c,11f,15], N-(2,5-dibromo-6-methoxypyridin-3-yl)benzamide
2ah was selected as the target product (Scheme 2). Utilizing our
Scheme 2. Various synthetic routes to ortho-bromoanilide 2ah.
heterocyclic arylhydroxylamines, such as dibenzofuran and pyri-
dine aromatics (Table 2, entries 33–35). The excellent ortho-regios-
electivity and structure of the product was determined by X-ray
analysis of 2ah (Table 2, entry 34). In addition, this transformation
could also be applied to the modification of nature products rele-
vant molecules, such as menthol, fenchol and borneol derivatives
(Table 2, entries 36–38).
Scheme 3. Gram scale reaction and control experiment. BHT = butylated
hydroxytoluene.
3

Y. Du, Z. Xi, L. Guo et al.
Tetrahedron Letters 72 (2021) 153074
Acknowledgments
We gratefully acknowledge Shandong University, the National
Natural Science Foundation of China (21702122), the Key Technol-
ogy Research and Development Program of Shandong Province
(2019GSF108056)), Major Scientific and Technological Innovation
Projects of Shandong Province (2019JZZY010503) and Key
Research and Development Plan of Shandong Province
(2019QYTPY02) for financial support. We thank Prof. Di Sun at
Shandong University for assistance with the X-Ray crystal diffrac-
tion and data analysis.
Scheme 4. Proposed mechanism.
Appendix A. Supplementary data
optimized reaction conditions, the desired ortho-bromoanilide 2ah
could be obtained with a two-step yield of 41%, while the literature
methods gave lower yields. These results indicated that our
method provided a complementary tool to access ortho-bro-
moanilides that were difficult to prepare.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153074.
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insights of this transformation, control experiment was conducted
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HBr in the system and produces water, which could cause the
hydrolysis of SOBr2 and lead to the decrease in yield of the
reactions.
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