Gold(iii)-catalyzed halogenation of aromatic boronates with N -halosuccinimides

Article abstract of DOI:10.1021/ol102350v

Aromatic boronates bearing halogen substituents in the aromatic ring can be synthesized by AuCl₃-catalyzed halogenations with N-halosuccinimides.

Full text of DOI:10.1021/ol102350v

ORGANIC
LETTERS
2010
Vol. 12, No. 23
5474-5477
Gold(III)-Catalyzed Halogenation of
Aromatic Boronates with
N-Halosuccinimides
Di Qiu, Fanyang Mo, Zhitong Zheng, Yan Zhang, and Jianbo Wang*
Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of
Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of
Chemistry, Peking UniVersity, Beijing 100871, China
wangjb@pku.edu.cn
Received September 29, 2010
ABSTRACT
Aromatic boronates bearing halogen substituents in the aromatic ring can be synthesized by AuCl3-catalyzed halogenations with
N-halosuccinimides.
Functionalized aromatic boronic acids and esters have
attracted great attention in recent years because of their
extensive application in organic synthesis as well as in other
fields.1,2 Aromatic boronates bearing halogen substituents are
particularly valuable because multiple Suzuki-Miyaura
cross-coupling reactions are possible from such compounds.3
Halogen-substituted arylboronic compounds have been com-
monly synthesized by selective monoborylation of aromatic
substrates bearing more than one halide.4 Apparently, this
approach is limited in scope by the availability of multih-
alogen-substituted aromatic starting materials as well as by
the difficulties associated with the selective monoborylation.
Recently, direct C-H borylation of mono- and dihaloarenes
has been developed into a useful method for preparing
haloarylboronates.5
On the other hand, halogenation of arylboronic compounds
would be an attractive alternative approach to access these
arylboronic compounds. Although arylboronic compounds
are relatively stable in general, their further derivatization
has been found difficult due to the chemical property of the
boron group that makes them reactive toward commonly used
organic reagents. In particular, protodeboronation or ipso
substitution of the boron group easily occurs.6 For this reason,
halogenation of arylboronic acid derivatives has been rarely
documented in the literature. In 1961, Kuivila and co-workers
reported AcOH-mediated bromination and chlorination of
(1) For selected reviews, see: (a) Suzuki, A. Acc. Chem. Res. 1982, 15,
178. (b) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (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
.
(2) Hall, D. G. Boronic Acids; Wiley-VCH: Weinheim, 2005
.
(3) (a) Wang, C.; Glorius, F. Angew. Chem., Int. Ed. 2009, 48, 5240.
(b) Tobisu, M.; Chatani, N. Angew. Chem., Int. Ed. 2009, 48, 3565.
(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.;
Nosaka, K.; Akaji, K. Bioorg. Med. Chem. 2009, 17, 5769.
(5) For a recent review, see: Mkhalid, I. A. I.; Barnard, J. H.; Marder,
T. B.; Murphy, J. M.; Hartwig, J. F. Chem. ReV. 2010, 110, 890.
(6) For examples, see: (a) Kabalka, G. W.; Sastry, K. A. R.; Sastry, U.;
Somayaji, V. Org. Prep. Proced. Int. 1982, 14, 359. (b) Thiebes, C.; Prakash,
G. K. S.; Petasis, N. A.; Olah, G. A. Synlett 1998, 2, 141. (c) Szumigala,
R. H., Jr.; Devine, P. N.; Gauthier, D. R., Jr.; Volante, R. P. J. Org. Chem.
2004, 69, 566. (d) Thompson, A. L. S.; Kabalka, G. W.; Akula, M. R.;
Huffman, J. W. Synthesis 2005, 547. (e) Murphy, J. M.; Liao, X.; Hartwig,
J. F. J. Am. Chem. Soc. 2007, 129, 15434. (f) Wu, H.; Hynes, J., Jr. Org.
Lett. 2010, 12, 1192.
10.1021/ol102350v  2010 American Chemical Society
Published on Web 11/11/2010

arylboronic acids. The reaction is only limited to methoxy-
substituted arylboronic acids.7 More recently, Hall and co-
workers reported a Ag(I)-mediated iodination and bromina-
tion of arylboronic acids.8 The reaction occurs under mild
conditions (25 °C) and is regioselective. However, this
reaction is generally restricted to arylboronic acids bearing
electron-donating substituents, and moreover, a stoichiomet-
ric amount of silver salt is used.
and FeBr3, which are commonly used as Lewis acid catalysts
in halogenation reactions, only afforded conversion of 51%
and 12%, respectively, even with a catalyst loading of 20
mol % (Table 1, entries 2 and 3), while BF3·OEt2 only
afforded a conversion of less than 5% (entry 4). NH4NO3,
which has been an efficient catalyst in this type of reaction
as reported by Tanemura and co-workers,10a was not efficient
(entry 5). Moreover, we found that neither AlCl3 nor H2SO4
was active in this reaction (entries 6 and 7). Finally, control
experiments in the absence of AuCl3 demonstrate that Au
catalyst is required for the halogenation (entry 8).
We9 have recently reported a highly efficient AuCl3-
catalyzed halogenation of aromatics by N-bromo-, N-iodo-,
and N-chlorosuccinimide (NBS, NIS, and NCS, respec-
tively).10,11 The halogenation conditions are mild, and in
particular, the catalyst loading of AuCl3 is very low
(0.01-1.0 mmol %). In this paper, we further demonstrate
that AuCl3 can also be used for the halogenation of
arylboronates. The reaction is highly efficient and demon-
strates high regioselectivities in most cases.
At the outset, we observed with delight that the bromi-
nation of pinacol benzylboronate with NBS occurs efficiently
with 2 mol % AuCl3 in ClCH2CH2Cl (DCE) at 60 °C (Table
1, entry 1). However, the regioselectivity is rather low, with
With the efficient AuCl3-catalyzed halogenations being
confirmed, we then proceeded to study the scope of the
reaction.12 A variety of arylboronate substrates have been
subjected to the reaction and the data are shown in Table 2.
The results show that AuCl3 could catalyze a wide range of
arylboronates, including these bearing heterocyclic rings
(entries 13, 14, and 20). Moreover, the reaction works well
with arylboronates bearing electron-withdrawing substituents
on aromatic rings, although higher catalyst loading and
reaction temperature as well as longer reaction times are
required in these cases (entries 7-12). It was particularly
noted that temperature was an important factor for the
reaction. Depending on the substrates, the reaction temper-
ature needs to be adjusted to enable complete bromination.
Moreover, high temperature in some cases led to multiha-
logenation. It has been noted that the 2-position of thiophene
is more active so the bromination or iodination occurs at
the 2-position preferentially (entries 13, 14, and 20). The
low yield in the case of 1m is due to the ipso substitution of
the boron group by the bromine (entry 13).
Table 1. Bromination of Pinacol Phenylboronate Using Various
Catalystsa
entry
catalyst (mol %)
conversionb (%)
1
2
3
4
5
6
7
8
AuCl3 (2)
100
51
12
<5
<5
<5
<5
<5
FeCl3 (20)
FeBr3 (20)
BF3•OEt2 (20)
NH4NO3 (20)
AlCl3 (20)
H2SO4 (20)
none
The structures of the halogenation products have been
established by spectra data.13 Moreover, four of them are
further confirmed by X-ray crystallographic analyses of the
products (2a, 2f) or their corresponding hydrolyzed acids
(2b′, 2q′) (Figure 1).
An interesting question in the halogenation of arylbor-
onates concerns the property of the boronate group in
affecting the halogenation activity and regioselectivity. We
proceeded to investigate this issue by comparing the halo-
genation of benzene and pinacol phenylboronate under
identical conditions. The data collected in Table 3 demon-
strate that the pinacol boronate group is a weak activating
group (compare entries 1-4). Next, we found that in the
bromination of phenylboronate the corresponding products
could be isolated in 75% yield as regioisomers. The ratio of
ortho/meta/para is nearly 1:1:1 as detected by 1H NMR. The
directing effect of boron is obscure with the ratio of ortho
+ para versus meta being approximately 2:1, which means
meta is slightly disfavored.
a Reaction conditions: PhBpin (1 mmol), NBS (1.2 mmol), DCE (2
mL), 60 °C, 6 h. b Conversion was determined by GC-MS with n-dodecane
as the internal standard. DCE: 1,2-dichloroethane. NBS: N-bromosuccinimide.
the ratio of ortho/meta/para being nearly 1:1:1. We pro-
ceeded to compare other typical Lewis acid catalysts that
have been widely used for bromination with NBS. The results
summarized in Table 1 clearly demonstrate that AuCl3 has
much higher efficiency. Strong Lewis acids, such as FeCl3
(7) Kuivila, H. G.; Benjamin, L. E.; Murphy, C. J.; Price, A. D.; Polevy,
J. H. J. Org. Chem. 1962, 27, 825.
(8) Al-Zoubi, R. M.; Hall, D. G. Org. Lett. 2010, 12, 2480.
(9) Mo, F.; Yan, J. M.; Qiu, D.; Li, F.; Zhang, Y.; Wang, J. Angew.
Chem., Int. Ed. 2010, 49, 2028.
The experiments suggest that the pinacol boronate group
is a weakly activating and ortho/para-directing group. This
may be explained by the following reasoning. First, boron
(10) For examples of halogenations with NXS, see: (a) Tanemura, K.;
Suzuki, T.; Nishida, Y.; Satsumabayashi, K.; Horaguchi, T. Chem. Lett.
2003, 32, 932. (b) Zhang, Y.; Shibatomi, K.; Yamamoto, H. Synlett 2005,
2837. (c) Zysman-Colman, E.; Arias, K.; Siegel, J. S. Can. J. Chem. 2009,
87, 440
.
(11) For examples of tramsition-metal-catalyzed halogenation with NXS,
see: (a) Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford, M. S. Org. Lett.
2006, 8, 2523. (b) Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford, M. S.
(12) For the reaction scope of the boron group, see the Supporting
Information.
(13) For details of the structure characterization, see the Supporting
Information.
Tetrahedron 2006, 62, 11483
.
Org. Lett., Vol. 12, No. 23, 2010
5475

Table 2. AuCl3-Catalyzed Halogenation of Pinacol Arylboronatesa
a Reaction conditions: ArBpin (1 mmol), NXS (1.2 mmol), DCE (2 mL). b Isolated yield. c 1.0 equiv of NXS was used. d 2.4 equiv of NXS was used.
has smaller value of electronegativity than carbon (2.04
versus 2.55). Consequently, the inductive effect of boron is
electron-donating. On the other hand, since boron has an
empty p-orbital, the resonance effect is electron-withdrawing.
However, the boron may be complexed with a Lewis base
(such as carbonyl oxygen of succinimide) in the reaction
system, which may counteract the electron-withdrawing
effect.14
Since the electronic effect of the pinacol boronate group is
rather weak, the regioselectivity of the Au-catalyzed bromination
is controlled by other substituents on the aromatic ring in most
cases. For example, even a weak directing group such as a
methyl in the aromatic ring overrides the pinacol boronate group
(14) For a discussion of electronic effects of boron groups, see: Entwistle,
C. D.; Marder, T. B. Chem. Mater. 2004, 16, 4574.
5476
Org. Lett., Vol. 12, No. 23, 2010

Scheme 1. Application of Halogenated Arylboronic Compounds
in Consecutive Suzuki-Miyaura Cross-Coupling
p-tert-butylphenylboronate 1o indicates steric effects also play
an important role (Table 2, entry 15). Interestingly, there is an
obvious trend that halogenation occurs favorably at the position
ortho to the boron substituent. A similar ortho directing effect
has also been observed in Hall’s Ag-mediated halogenation
reaction.8
The halogenated arylboronic compounds are valuable in
organic synthesis. To demonstrate the utility of the products,
wehavecarriedoutexperimentsofconsecutiveSuzuki-Miyaura
coupling reactions (Scheme 1). Thus, starting from 2h and
2p, substituted o-terphenyl products 4a-d could be prepared
in two steps in high yields.
Figure 1. X-ray structures of 2a, 2f, 2b′, and 2q′.
Table 3. Comparison of the Reactivity in AuCl3-Catalyzed
Brominationa
In conclusion, we have developed an efficient catalytic
halogenation reaction of arylboronates. It has the advantages
of low catalyst loading, mild halogenation conditions, and
generally good yields and high regioselectivity. This reaction
provides an easy approach toward functionalized arylbor-
onates that are otherwise difficult to access.
entry
substrate, R )
temp (°C)
t (h)
conversionb (%)
1
2
3
4
5
6
H
H
Bpin
Bpin
H
40
40
40
40
60
60
6
24
6
24
6
15
30
24
46
42
Acknowledgment. This project was supported by the
NSFC(GrantNos.20902005,20832002,20772003,20821062)
and 973 Program (No. 2009CB825300).
Bpin
6
>99
a Reaction conditions: R-Ph (1 mmol), NBS (1.1 mmol), DCE (2 mL).
b Conversion was determined by GC-MS with n-dodecane as the internal
standard.
Supporting Information Available: Experimental pro-
1
cedure, characterization data, and H and 13C NMR spectra
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
to control the regioselectivity of bromination (Table 2, entry
3). The bromination selectivity of the reaction with pinacol
OL102350V
Org. Lett., Vol. 12, No. 23, 2010
5477