Palladium-catalyzed ortho-C(sp2)[sbnd]H bromination of benzaldehydes via a monodentate transient directing group strategy

Article abstract of DOI:10.1016/j.tetlet.2019.151263

A facile and efficient monodentate transient directing group strategy was developed to enable the palladium-catalyzed ortho-C(sp²)[sbnd]H bromination of benzaldehydes. A broad scope of benzaldehydes were transformed into the desired products by employing 2-amino-5-chlorobenzotrifluoride as a monodentate transient directing group, demonstrating good functional group tolerance. Mild reaction conditions and no requirement for a silver salt are also features of this strategy.

Full text of DOI:10.1016/j.tetlet.2019.151263

Journal Pre-proofs
Palladium-catalyzed ortho-C(sp2)−H bromination of benzaldehydes via a mon-
odentate transient directing group strategy
Qiyun Yong, Bing Sun, Fang-Lin Zhang
PII:
S0040-4039(19)31041-X
https://doi.org/10.1016/j.tetlet.2019.151261
TETL 151263
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 September 2019
5 October 2019
10 October 2019
Please cite this article as: Yong, Q., Sun, B., Zhang, F-L., Palladium-catalyzed ortho-C(sp2)−H bromination of
benzaldehydes via a monodentate transient directing group strategy, Tetrahedron Letters (2019), doi: https://doi.org/
10.1016/j.tetlet.2019.151261
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Palladium-catalyzed ortho-C(sp2)‒H
bromination of benzaldehydes via a
monodentate transient directing group
strategy
Leave this area blank for abstract info.
Qiyun Yong, Bing Sun and Fang-Lin Zhang
monodentate TDG
CF3
NH2
[Pd]
O
O
R
R
NBS
Br
H
Cl
via
R
R'
N
R = Br, Cl, F, NO2, CH3O
20 - 98% yield
[Pd]

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Palladium-catalyzed ortho-C(sp2)−H bromination of benzaldehydes via a
monodentate transient directing group strategy
Qiyun Yong,a Bing Suna,  and Fang-Lin Zhanga, 
a School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan 430070, PR China
———
ARTICLE INFO
ABSTRACT
 Corresponding author. e-mail: bing.sun@whut.edu.cn (B. Sun)
 Corresponding author. e-mail: fanglinzhang@whut.edu.cn (F.-L. Zhang)
Article history:
Received
A facile and efficient monodentate transient directing group strategy was developed to enable
the palladium-catalyzed ortho-C(sp2)‒H bromination of benzaldehydes. A broad scope of
Received in revised form
Accepted
benzaldehydes were transformed into the desired products by employing 2-amino-5-
chlorobenzotrifluoride as
a monodentate transient directing group, demonstrating good
Available online
functional group tolerance. Mild reaction conditions and no requirement for a silver salt are also
features of this strategy.
2009 Elsevier Ltd. All rights reserved.
Keywords:
Palladium
Monodentate
Transient directing group
Benzaldehyde
a) Representative pharmaceutical compounds containing an aryl bromide
1. Introduction
Br
F
S
Aryl halides are widely utilized as important precursors for
organometallic reagents as well as transition-metal-catalyzed
cross-coupling partners.1 In addition to these general features,
aryl bromides are considered as building blocks for valuable
classes of pharmaceutical compounds. Bromhexine, bearing an
aryl dibromide subunit, is well known as an expectorant in the
treatment of respiratory disorders and mucus.2 Bromperidol is a
bromine analog of haloperidol hydrochloride, which acts as an
antipsychotic in the treatment of schizophrenia.3 Brotizolam is a
Br
N
N
N
N
HO
O
N
N
Br
NH2
Br
Cl
bromhexine
bromperidol
brotizolam
b) Pd-catalyzed ortho-C–H bromination via a bidentate TDG strategy
[Pd]
AgTFA
via
O
O
N
O
R
R
R
C
O
sedative-hypnotic drug with
a
thienodiazepine bromide
Bidentate TDG
90 ºC
Br
[M]
H
H
pharmacophore (Scheme 1a).4 The growing practical value of
aryl bromides has attracted extensive attention toward their
efficient synthesis.5
c) Pd-catalyzed ortho-C–H bromination via a monodentate TDG strategy
via
R'
[Pd]
O
O
N
In recent years, transition-metal-catalyzed transient-directing-
group (TDG)-mediated C−H functionalization has emerged as a
powerful tool to access complex molecules.6 Pioneering work by
the Yu group disclosed that amino acids could be employed as
bidentate TDGs for the Pd-catalyzed C(sp3)−H arylation of o-
alkyl benzaldehydes and ketones, featuring no auxiliary
installation and the removal of stoichiometric directing groups.7
Subsequently, a set of nitrogen-based small molecules were
R
R
R
Monodentate TDG
60 ºC
Br
H
[M]
Scheme 1. Representative pharmaceuticals containing aryl
bromides (a), the previously reported synthetic approach (b),9 and
the present work (c).
An example was demonstrated in a collaborative report by Yu
and our group, where the ortho-C(sp2)−H bromination of a broad
scope of benzaldehydes were catalyzed by Pd with 4-
reported as suitable bidentate TDGs for diverse C–H
Reference source not found.
functionalizations.Error!
However, the
nitroanthranilic acid as
a
bidentate TDG (Scheme 1b).8
transition metal-catalyzed bromination of C(sp2)–H bonds via
Nevertheless, this bidentate TDG pattern typically requires an in
situ formed neutral imine coordinating site and a second
coordinating site on the directing group to form the reactive
metallocycle species. Meanwhile, the addition of a silver salt
reduced the atom-economy of this strategy. Alternatively, the
monodentate TDG strategy, where an in situ formed imine could
be directly coordinated to transition metals to access the
bidentate TDG remains rare.

2
metallocycle, represents a simplified method for Pd-catalyzed C–
H functionalization. Recently, we reported the Pd-catalyzed
ortho-C−H methoxylation and chlorination of benzaldehydes by
employing 3-(trifluoromethyl)-aniline as a monodentate TDG,
either with or without the assistance of an external ligand, where
a broad product scope was obtained with moderate to excellent
yields.10 To the best of our knowledge, there are no reports
covering Pd-catalyzed C–H bromination via monodentate TDG
strategies. Therefore, in this work we report the facile and
efficient Pd-catalyzed ortho-C(sp2)‒H bromination of
benzaldehydes via a monodentate TDG strategy under mild
reaction conditions without the addition of silver salts or an
external ligand (Scheme 1c).
TDG
O
O
O
Pd(OAc)2 10 mol%
TDG
CF3
Br
NH2
N Br
+
Solvent
Br
Br
Cl
O
60 °C, 24 h
1a
2
3a
T8
Yield 3a
(%)
Entry
Solvent (v:v)
NBS
(mol%)
30%
30%
30%
30%
30%
30%
30%
30%
30%
10%
20%
40%
1
2
3
DCE
1.5 eq.
1.5 eq.
1.5 eq.
1.5 eq.
1.5 eq.
1.5 eq.
1.5 eq.
1.0 eq.
1.2 eq.
1.2 eq.
1.2 eq.
1.2 eq.
NR
DCE:TFA=10:1
DCE:TFA=5:1
DCE:TFA=4:1
DCE:TFA=1:1
TFA
DCE:HOAc=5:1
DCE:TFA=5:1
DCE:TFA=5:1
DCE:TFA=5:1
DCE:TFA=5:1
DCE:TFA=5:1
77%
80%
74%
71%
68%
NR
4
5
6
7
2. Results and Discussion
We initiated our investigation by screening various
monodentate TDGs for the model reaction of m-
bromobenzaldehyde 1a (1.0 eq.) with N-bromosuccinimide 2
(NBS, 1.5 eq.) to afford 2,5-dibromobenzaldehyde 3a (Table 1).
The initial experiments were conducted with 10 mol% Pd(OAc)2
as catalyst and 30 mol% ligand in a mixed solvent of DCE and
TFA (v:v = 5:1) at 60 °C for 24 h. A series of anilines with
different substituents were tested as monodentate TDGs. 2-
Amino-5-chlorobenzotrifluoride (T8) proved to be the best TDG
for this reaction, affording the brominated product 3a in 80%
yield.
8
9
10
11
12
62%
83%
37%
86%
78%
a
Reagents and conditions: 1a (0.1 mmol), Pd(OAc)2 (10 mol%),
solvent, 60 °C, 24 h. Isolated yield after column chromatography.
With the optimized reaction conditions in hand, the substrate
scope was examined (Table 3). First, we evaluated the
compatibility of this strategy with various electron-donating or
electron-withdrawing mono-substituents at different positions of
the benzaldehydes, such as halogen (3a-e), methyl (3f), methoxy
(3g) and nitro (3h) groups at the ortho or meta sites. Generally,
moderate to good yields were obtained, except for the methoxy
and nitro groups which led to lower yields (3g-h). Additionally,
the position of the halogen substituent has no significant effect.
Good yields were obtained for disubstituted benzaldehydes with
different halogen groups (3i-l). For disubstituted benzaldehydes
containing both halogen and methyl groups, moderate yields
were obtained (3m-p). Dimethyl benzaldehyde substituted at
different positions gave moderate yields (3q-r), and trimethyl
benzaldehyde gave a low yield due to steric hindrance (3s). For
benzaldehydes with methoxy groups, moderate yields were
obtained (3t-w). 2-Naphthylbenzaldehyde also gave an excellent
yield (3x). The thiophene aldehyde underwent bromination in an
acceptable yield (3y), providing a potential candidate for the
synthesis of benzothiophene carboxamide derivatives for
application as inhibitors of plasmodium falciparum enoyl-ACP
reductase.11
Next, optimization of the reaction conditions was carried out.
As summarized in Table 2, the solvent screening showed that the
presence of TFA was essential to trigger the reaction, albeit
excess TFA inhibited the yields (Table 2, entries 1-7). A
maximum yield of 80% was obtained in the mixed solvent of
DCE and TFA (v:v = 5:1). Next, the amount of NBS was
examined to improve the yield. Gratifyingly, lowering the
amount of NBS to 1.2 eq. was beneficial to the reaction (Table 2,
entry 9). However, lowering the amount of NBS (1.0 eq.) sharply
decreased the yield (Table 2, entry 8). Finally, we optimized the
amount of TDG (T8) and observed that 20 mol% gave the best
yield (Table 2, entry 11). More or less T8 was unfavorable to
promoting the reaction (Table 2, entries 10 and 12).
Table 1. Transient directing group screening.a
O
O
O
Pd(OAc)2 10 mol%
TDG 30 mol%
Br
Cl
H
N
Br
+
DCE:TFA = 5:1
60 °C, 24 h
Br
Br
O
3a
1a
NH2
2
NH2
NH2
NH2
Next, we examined the utility of the monodentate TDG
strategy in the dibromination of benzaldehydes, which can be
potentially applied for diverse late-stage functionalizations to
access complex bioactive molecules.12 As shown in Table 4, a
low yield (29%) was obtained for dibromination product 5a when
1.5 eq. NBS was used (Table 4, entry 1). When the amount of
NBS was increased to 2.5 eq., an excellent yield of 73% was
obtained (Table 4, entry 4).
F
F
F
F
F3C
CF3
CF3
NO2
CF3
T1
52%
T2
T3
T4
23%
27%
18%
NH2
NH2
NH2
CF3
Br
NH2
CF3
40%
F3C
CF3
35%
F3C
O
Cl
Under the optimal reaction conditions, the substrate scope for
dibromination was examined to introduce two bromine atoms at
ortho positions (Table 5). For benzaldehydes bearing methyl
(5a), benzyl (5b) and methyl 4-methylbenzoate (5c) substituents
at the para position, the electronic properties exerted negligible
effects on the reactivity and selectivity. The desired products
were afforded with good to excellent yields (67-82%).
T5
T6
T7
T8
80%
38%
a
Reagents and conditions: 1a (0.1 mmol), 2 (1.5 eq.), Pd(OAc)2
(10 mol%), TDG (30 mol%), DCE (1 mL), TFA (0.2 mL), 60 °C,
24 h. Isolated yield after column chromatography.
Table 3. Scope of the ortho-C(sp2)−H bromination of
benzaldehydes.a
Table 2. Optimization of the reaction conditions.a

3
O
O
O
O
O
CF3
O
Pd(OAc)2 10 mol%
TDG 20 mol%
CF3
Pd(OAc)2 10 mol%
TDG 20 mol%
Br
Br
NH2
NH2
Br
+
+
N Br
N Br
R
R
Cl
DCE:TFA = 5:1
DCE:TFA = 5:1
60 °C, 24 h
Cl
O
O
2.5 eq.
2
R
R
TDG
1.0 eq.
1.2 eq.
60°C
24h
TDG
Br
1
2
3
4
5
O
O
O
O
O
Br
Br
O
O
O
O
Br
Br
Cl
Br
Br
Br
F
Br
O
Br
Cl
Br
Br
Br
b
3a
3b
3g
3c
3e
3j
86%
O
76%
O
63%
O
3d
88%
54%
5a
5b
5c
67%
73%
82%
O
O
Br
Br
Br Cl
Cl
Br
Br
a
Reagents and conditions: 4 (0.4 mmol), 2 (2.5 eq.), Pd(OAc)2
(10 mol%), TDG (20 mol%), DCE (2.5 mL), TFA (0.5 mL), 60
°C, 24 h. Isolated yield after column chromatography.
Br
O
O2N
3h
F
59%
b
b
3f
20%
O
34%
O
3i
80%
O
98%
O
O
Br
Br
Br
Br
Br
F
Acknowledgments
Cl
Cl
F
Cl
Cl
Br
We are grateful for financial support from the National
Natural Science Foundation of China (no. 21703162, 21971200)
and the Natural Science Foundation of Hubei Province
(2018CFB505).
b
b
3k
3l
3m
53%
54%
69%
3n
3s
3o
80%
O
57%
O
O
O
O
O
Br
Br
Br
Br
Br
O
F
References and notes
b
b
3p
36%
O
3q
3r
3t
50%
87%
O
37%
76%
O
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O
O
Br
Br
Br
Br
Br
Br
S
Br
O
O
O
O
3u
3v
3w
3x
3y
30%
87%
53%
30%
90%
mono:di=1:1.1 mono:di=1:1.5
a
Reagents and conditions: 1 (0.4 mmol), 2 (1.2 eq.), Pd(OAc)2
(10 mol%), TDG (20 mol%), DCE (2.5 mL), TFA (0.5 mL), 60
°C, 24 h. Isolated yield after column chromatography. 1 (0.2
b
mmol), 2 (1.2 eq.), Pd(OAc)2 (10 mol%), TDG (20 mol%), DCE
(1 mL), TFA (0.2 mL), 60 °C, 24 h.
2.
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Table 4. Optimization of the reaction conditions.a
O
O
O
CF3
Pd(OAc)2 10 mol%
TDG 20 mol%
4.
5.
Br
Br
NH2
+
N Br
DCE:TFA = 5:1
60 °C , 24 h
Cl
O
TDG
4a
2
5a
Entry
NBS
Yield 5a (%)
29%
1
2
3
4
1.5 eq.
2.0 eq.
2.3 eq.
2.5 eq.
42%
65%
73%
a
Reagents and conditions: 4a (0.1 mmol), 2, Pd(OAc)2 (10
mol%), TDG (20 mol%), DCE (1 mL), TFA (0.2 mL), 60 °C, 24
h. Isolated yield after column chromatography.
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3. Conclusion
We have developed an efficient Pd-catalyzed ortho-C(sp2)‒H
bromination of benzaldehydes via a monodentate TDG strategy
which proceeds under mild conditions without the addition of
silver salts or an external ligand.
7.
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Scope of the ortho-C(sp2)−H dibromination of benzaldehydesa

4
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Highlights


An efficient monodentate transient
directing group strategy was developed.
Ortho-C‒H bromination of
9. Liu, X.H.; Park, H.; Hu, J.H.; Hu, Y.; Zhang, Q.L.; Wang, B.L.;
Sun, B. Yeung, K.S. Zhang, F.L.; Yu, J.Q. J. Am. Chem. Soc.
2017, 139, 888-896.
benzaldehydes was catalyzed by Pd via
Monodentate TDG.
Mild reaction conditions and no addition
of silver salt are featured.
10. Li, F.; Zhou, Y.; Yang, H.; Wang, Z.Q.; Yu, Q.Q.; Zhang, F.L.
Org. Lett. 2019, 21, 3692-3695.
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Soltis, M.; Elder, J.H.; Olson, A.J.; Stout, C.D. Chem. Biol. Drug
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2014, 70, 5128-5135.

Supplementary data
Graphical Abstract
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template box below.
Supplementary data associated with this article can be found
in the online version containing experimental procedures and
characterization data for all new compounds.
Fonts or abstract dimensions should not be changed or altered.
Palladium-catalyzed ortho-C(sp2)‒H
bromination of benzaldehydes via a
monodentate transient directing group
strategy
Leave this area blank for abstract info.
Qiyun Yong, Bing Sun and Fang-Lin Zhang
monodentate TDG
CF3
[Pd]
O
O
NH2
R
R
NBS
H
Br
Cl
via
R'
N
R = Br, Cl, F, NO2, CH3O
20 - 98% yield
R
[Pd]