Metal-free halogenation of arylboronate with N-halosuccinimide

Article abstract of DOI:10.1016/j.tetlet.2014.06.003

Efficient bromination and chlorination of aryl pinacol boronates were accomplished without the addition of metal reagent. The reaction proceeded efficiently with electron-rich arylboronates or heteroarylboronates in DMF or acetonitrile, to afford mono-, di-, or trihalogenated aryl pinacol boronates.

Full text of DOI:10.1016/j.tetlet.2014.06.003

Accepted Manuscript
Metal-free halogenation of arylboronate with N-halosuccinimide
Toshiyuki Kamei, Aoi Ishibashi, Toyoshi Shimada
PII:
S0040-4039(14)00982-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.06.003
TETL 44727
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
28 April 2014
28 May 2014
3 June 2014
Please cite this article as: Kamei, T., Ishibashi, A., Shimada, T., Metal-free halogenation of arylboronate with N-
halosuccinimide, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.06.003
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Metal-free halogenation of arylboronate with
N-halosuccinimide
Toshiyuki Kamei*, Aoi Ishibashi, Toyoshi Shimada *

1
Tetrahedron Letters
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Metal-free halogenation of arylboronate with N-halosuccinimide
Toshiyuki Kamei∗, Aoi Ishibashi and Toyoshi Shimada∗
Department of Chemical Engineering, Nara National College of Technology, 22 Yata-cho, Yamatokoriyama, Nara 639-1080, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Efficient bromination and chlorination of aryl pinacol boronates was accomplished without the
addition of metal reagent. The reaction proceeded efficiently with electron-rich arylboronates or
heteroarylboronates in DMF or acetonitrile, to afford mono-, di-, or trihalogenated aryl pinacol
boronates.
Received in revised form
Accepted
Available online
2013 Elsevier Ltd. All rights reserved.
Keywords:
halogenation
aryl boronate
N-halosuccinimide
electrophilic substitution
Functionalization of aryl boronic acids and esters has attracted
great interest because the products are widely applicable to the
Table 1. Screening of boronic esters for bromination reactions
synthesis of complex organic molecules.1,2
Halogenated
arylboronates, especially, are useful building blocks for the
synthesis of arene-based pharmaceutical compounds through
multiple Suzuki-Miyaura cross-coupling reactions.3,4,5 Although
the borylation of haloarenes was developed for the synthesis of
haloarylboronates,3,4 the reverse method, the halogenation of
Entry
1
Borane
Result
arylboronates, is less developed.5,6
Difficulties in the
no reaction
halogenation of arylboronates result from the high reactivity of
the C-B bond toward electrophiles, which results in ipso-
substitution. Olah et al. reported the reaction of arylboronic
acids with N-halosuccinimide (NBS) to afford haloarenes;7
Szumigala et al. reported a similar reaction with N,N’-dibromo-
5,5-dimethylhidantoin (DBH).8 For this reason, studies on the
halogenation of arylboronic acids or boronates have been rarely
reported. In 1962, Kuivila reported the bromination of 3-
anisylboronic acid with bromine in acetic acid.5a Recently,
silver-mediated halogenation of arylboronic acids and gold-
catalyzed halogenation of arylboronates were reported by Hall5b
2
3
no reaction
complex mixture
4
5
complex mixture
69%
and Wang,5c respectively.
These reactions were effective
methods for the preparation of halogenated arylboronates.
However, they required metal reagents to afford the desired
products. The present report describes the development of a
convenient and effective method for the synthesis of halogenated
arylboronates without the addition of a metal reagent.
First, the bromination of 3-anisylboronic acid derivatives with
NBS as a bromonium cation source in DMF was examined
(Table 1).9 Unfortunately, boronic acid did not undergo
bromination successfully (Table 1, entry 1). The DAN(1,8-
———
∗ Corresponding author. Tel.: +81-743-55-6155; fax: +81-743-55-6169; e-mail: kamei@chem.nara-k.ac.jp (T. Kamei), shimada@chem.nara-
k.ac.jp (T. Shimada)

2
Tetrahedron
diaminonaphthalene)-protected boronic acid10 also was
successful and afforded 1 in high yield (Table 3, entry 7).
Addition of excess NBS improved the yield of 1 to 87% (Table 3,
entry 9).
recovered after reaction (Table 1, entry 2). Use of MIDA (N-
methyliminodiacetic acid) boronate11 (Table 1, entry 3) or
trifluoroborate12,13 (Table 1, entry 4) resulted in decomposition to
afford a complex mixture of products. However, use of pinacol
boronate produced pinacol 2-bromo-5-methoxyphenylboronate
(1) in 69% yield (Table 1, entry 5).
Table 4. Bromination of pinacol arylboronatesa
Entry
ArB(pin)
Product
Yield (%)
87
Next, bromonium cation sources were investigated. DBH
(Table 2, entry 2) and N-bromophthalimide (NBP) (Table 2,
entry 3) acted as bromonium cation sources to afford 1, albeit in
lower yield.
1b
2
3
39
Table 2. Screening of brominum cation sources for
bromination reactions.
(95)
4
5
-
-
0
0
Entry
Br+
NBS
DBHa
NBP
NMR yield (%)
1
81
52
40
2
3
a 0.55 equiv.
6c
7b
8
75
90
50
Table 3. Screening of solvents for bromination reactions
Entry
Solvent
DMF
NMR yield (%)
1
2
81 (69)c
CH2Cl2
hexane
THF
19
3
no reaction
4
38
9b
56
91
5
EtOH
NMP
5
9
6
7
CH3CN
DMF
80
10c
8a
9b
82
DMF
93 (87) c
a NBS (1.5 equiv.) b NBS (2.2 equiv.)
c Isolated yield in parentheses
11
12b
13b
13
65
38
The effect of the solvent was important in promotion of the
reaction (Table 3). Reaction in dichloromethane, which is a
common solvent for electrophilic bromination of aromatic
compounds, resulted in lower reactivity to give the product in
19% yield (Table 3, entry 2). The reaction performed in hexane
did not proceed, and only pinacol 3-anisylboronate was
recovered (Table 3, entry 3). In other solvents, such as THF,
ethanol, and NMP (N-methylpyrrolidone), lower reactivity was
observed (Table 3, entry 4-6). Reaction in acetonitrile was

3
a
Reactions were performed using pinacol aryl borate (50 mg) and NBS
c
NBS (3.3
4b
5c
6d
66
40
39
b
(1.1 equiv) in DMF (1 mL) at rt for 14 h. NBS (2.2 equiv.)
equiv.)
Substrate scope was then investigated (Table 4). Reaction of
pinacol 2-anisylboronate succeeded to give pinacol 2-methoxy-5-
bromophenylboronate in 39% yield (Table 4, entry 2). Reaction
of pinacol 4-anisylboronate resulted in ipso-substitution to afford
4-bromoanisole (Table 4, entry 3). Arylboronates containing a
slightly electron-rich substituent, such as pinacol 3-tolylboronate
and pinacol 3,5-dimethylphenylboronate, failed to undergo a
similar bromination (Table 4, entry 4-5).
In contrast,
7d
70
bromination was successful with more electron-rich
arylboronates to afford the corresponding products (Table 4,
entry 6-13). Bromination of pinacol 3-hydroxyphenyl boronate
gave the mixture of mono-, di-, and tribrominated compounds.
Treatment of 3.3 equiv. of NBS afforded pinacol 2,4,6-tribromo-
3-hydroxyphenylboronate in 75% yield (Table 4, entry 6).
Reaction of pinacol 3,5-dimethoxyphenylboronate with 1.1
equiv. of NBS also could not be controlled and afforded a
mixture of mono- and dibrominated products. Using 2.2 equiv.
of NBS alleviated this problem, giving pinacol 2.6-dibromo-3-
a
Reactions were performed using pinacol arylborate (50 mg) and NCS
b
c
(1.1 equiv) in DMF (1 mL) at rt for 14 h. NBS (2.2 equiv.) Reaction was
performed at 100°C. d Reaction was performed at 130°C.
Iodination also was examined by reaction of NIS with 3-anisyl
pinacol boronate. However, ipso-substitution occurred to give
iodoanisole as the sole product.6
In conclusion,
a general method for bromination and
hydroxyphenylboronate
and
pinacol
2,6-dibromo-3,5-
chlorination of pinacol arylboronates was developed. Although
the substrates applicable to this reaction were limited, reactions
proceeded without the need for a metal reagent, providing
halogenated arylboronates that are difficult to synthesize by other
methods.
dimethoxypnehylboronate as the sole product in 90% yield
(Table 4, entry 7). For pinacol 3-aminophenylboronate, the
bromination reaction could be controlled by adjusting the NBS
amount: 1.1 equiv. of NBS gave the monobrominated product in
50% yield (Table 4, entry 8), 2.2 equiv. of NBS produced the
dibrominated product in 56% yield (Table 4, entry 9), and 3.3
equiv. of NBS produced the tribrominated product in 91% yield
(Table 4, entry 10). Bromination of pinacol heteroarylboronates
also could be accomplished through reaction with NBS to afford
mono- or dibrominated compounds (Table 4, entry 11-13).
Reaction of pinacol 3-thiophenylboronate with 1 equiv. of NBS
resulted in a mixture of 2-brominated and 5-brominated products.
Reaction with 2 equiv. of NBS gave pinacol 2,5-dibromo-3-
thiopheneylboronate as the sole product.
Acknowledgments
The authors declare no competing financial interest.
References and notes
1. Hall, D. G. Boronic Acids; Wiley-VCH: Weinheim, 2005.
2. For selected reviews, see: (a) Suzuki, A. Acc. Chem. Res. 1982,
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(c) Miyaura, N. J. Organomet. Chem. 2002, 653, 54. (d) Miyaura,
N. Bull. Chem. Soc. Jpn. 2008, 81, 1535. (e) Merino, P.; Tejero, T.
Angew Chem. Int. Ed. 2010, 49, 7164.
Chlorination of aryl pinacol boronate was performed by
treatment of NCS (N-chlorosuccinimide) in DMF. Chlorination
was successful when using aryl pinacol boronates with highly
electron-donating substituents or heteroaryl pinacol boronates.
Some reactions were performed at elevated temperatures because
the reactivity of NCS was slightly lower than that of NBS (Table
5, entry 2-3 and 5-7).
3. For recent review, see: Mkhalid, I. A. I.; Barnard, J. H.; Marder,
T. B.; Murphy, J. M.; Hartwig, J. F. Chem. Rev. 2010, 110, 890.
4. For examples, see: (a) Kabalka, G. W.; Sastry, U.; Sastry, K. A. R.
J. Organomet. Chem. 1983, 259, 269. (b) Ishiyama, T.; Murata,
M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508. (c) Baron, O.;
Knochel, P. Angew. Chem., Int. Ed. 2005, 44, 3133. (d) Jiang, Q.;
Ryan, M.; Zhichkin, P. J. Org. Chem. 2007, 72, 6618. (e)
Ablordeppey, S. Y.; Altundas, R.; Bricker, B.; Zhu, X. Y.; Eyunni,
V. K.; Kumar, S.; Jackson, T.; Khan, A.; Roth, B. L. Bioorg. Med.
Chem. 2008, 16, 7291. (f) Konno, H.; Aimoto, S.; Smith, S. O.;
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Polevy, J. H. J. Org. Chem. 1962, 27, 825. (b) Al-Zoubi, R. M.;
Hall, D. G. Org. Lett. 2010, 12, 2480. (c) Qiu, D.; Mo, F.; Zheng,
Z.; Zhang, Y.; Wang, J. Org. Lett. 2010, 12, 5474.
Table 5. Chlorination of aryl pinacol boronatesa
Entry
ArB(pin)
Product
Yield
82
6. Iodination of pinacol 3,5-dimethoxyphenylphenyl boronate; Fuse,
S.; Sugiyama, S.; Takahashi, T. Chem. Asian J. 2010, 5, 2459.
7. Thiebes, C.; Prakash, G. K. S.; Petasis, N. A.; Olah, G, A. Synlett,
1998, 141.
1
8. Szumigala, R. H., Jr.; Devine, P. N.; Gauthier, D. R., Jr.; Volante,
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2a,c
87
48
9. Mitchell, R. H.; Lai, Y.-H.; Williams, R. V. J. Org. Chem. 1979,
44, 4733.
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Org. Lett. 2008, 10, 377.
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3b,c
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Darses, S.; Gemet, J.-P. Chem. Rev. 2008, 108, 288

4
Tetrahedron
13. C-C bond formation of heteroaryl trifluoroborate: Berionni, G.;
Morozova, V.; Heininger, M.; Mayer, P.; Knochel, P.; Mayr, H. J.
Am. Chem. Soc. 2013, 135, 6317.
was extracted with Et2O (10 ml x 3). The combined organic phase
was washed with H2O (10 ml x 2) and brine (10 ml x 1) and dried
over MgSO4. After removal of solvent under reduced pressure, the
residue was chromatographed on silica gel with Hexane to afford
2-bromo-5-methoxyphenyl pinacol borate (57.3 mg, 87% yield) as
colorless oil
14. General Procedure: To a solution of 3-anisyl pinacol borane (50
mg, 0.21 mmol) in DMF (1 mL) was added N-bromosuccinimide
(82 mg, 0.46 mmol). After stirring at room temperature for 14 h,
resultant solution was treated with 10% Na2S2O3 aq. (10 ml) and