Ruthenium-Catalyzed Ortho C(sp 2)-H Amidation of Benzaldehydes with Organic Azides

Article abstract of DOI:10.1055/s-0036-1591765

A ruthenium-catalyzed functionalization of benzaldehyde substrate with organic azides promoted by various transient directing groups has been developed. In this approach, C-H amination is achieved via a transient aldimine intermediate in good to excellent yields.

Full text of DOI:10.1055/s-0036-1591765

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–D
letter
A
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O. K. Rasheed, F.-l. Zhang
Letter
Synlett
Ruthenium-Catalyzed Ortho C(sp2)–H Amidation of Benzaldehydes
with Organic Azides
Omer K. Rasheed*a,b
CHO
R'SO2N3
CHO
Fang-lin Zhanga
[Ru(p-cymene)Cl2]2 (3 mol%)
AgSbF6 (5 mol%)
H
NHSO2R'
R
R
a School of Chemistry, Chemical Engineering and Life Sciences,
Wuhan University of Technology, Wuhan 430070, P. R. of China
b School of Chemistry, University of Montana, Missoula, MT
59812, USA
TDG (10 mol%)
50–97%
solvent, 80 °C, 12 h
14 examples
TDG: 3-(trifluoromethyl)aniline or 2-amino-4-(trifluoromethyl)benzoic acid
Omer.rasheed@mso.umt.edu
R' = Ts; SO2CH3; SO2(CH2)2CH3; SO2CH(CH3)2; SO2Ph; SO2C10H7
R = CH3; F; Cl; Br; I; 2,4-dimethyl; COOCH3; 2-methyl-4-bromo
Received: 20.11.2017
Accepted after revision: 29.01.2018
Published online: 16.02.2018
bility of the directing groups.11 Recently, Shi and co-work-
ers12 and others13,14 have reported an iridium-catalyzed
ortho C(sp2)−H amidation reaction of benzaldehydes with
various anilines by using a stoichiometric or catalytic di-
recting-group strategy [Scheme 1(B)]. Here, we report an
efficient method for the synthesis of 2-(sulfonyl-
amino)benzaldehydes by using an inexpensive ruthenium
complex to catalyze the ortho C(sp2)–H amidation of benz-
aldehydes with organic azides in the presence of catalytic
amount of 3-(trifluoromethyl)aniline (T3) and 2-amino-4-
(trifluoromethyl)benzoic acid (T10) as a transient directing
group (TDG) (Scheme 1).
DOI: 10.1055/s-0036-1591765; Art ID: st-2017-b0844-l
Abstract A ruthenium-catalyzed functionalization of benzaldehyde
substrate with organic azides promoted by various transient directing
groups has been developed. In this approach, C–H amination is
achieved via a transient aldimine intermediate in good to excellent
yields.
Key words C–H functionalization, directing groups, C–H activation,
ruthenium catalysis, amidation
Catalytic C–H bond functionalization with formation of
a C–C bond is attracting tremendous interest in synthesis,
as it can maximize atom and step economy.1 This method
simplifies chemical synthesis and it has the potential to re-
place classical catalytic cross-coupling reactions and free-
radical reactions.2,3 A variety of metal catalysts have been
reported to promote C–H bond activation and functional-
ization;4 initially, catalysts based on palladium or rhodium
were used, but more recently, catalysts based on iridium
(which is significantly less expensive than ruthenium) or
other metals have been used. In the past decade, a transi-
tion-metal-catalyzed ortho C(sp2)–H amidation of benzal-
dehydes has emerged as a powerful tool for the synthesis of
ortho-aminobenzaldehydes, which are important building
blocks for the synthesis of natural products, pharmaceuti-
cals, and organic materials.5
DG
DG
H
NHR
cat.
RN3
+
Directing group = imine, amide, ester, carboxylic acid etc.
Catalyst = Rh, Ru, Ir, Cu
A) Directing group strategy for amidation reaction
CHO
CHO
[Cp*IrCl2]2 (2–3 mol%)
H
NHSO2R
AgNTf2 (10 mol%)
RSO2N3
+
TDG 8 (10 mol%)
DCE, 80 °C, 24 h
TDG = 3-trifluoromethylaniline or 3,5-di(trifluoromethyl)aniline or
2-fluoro-5-trifluoromethylanilne 10 mol%
B) Transient directing group strategy for amidation reaction
CHO
CHO
[Ru(p-cymene)Cl2]2 (3 mol%)
NHSO2R
H
The groups of Chang,6 Jio,7 Bolm,8 and others9 have used
organic azides as amidating reagents in transition-metal-
catalyzed C–H amidation reactions. In this respect, many
directing groups and metal catalysts have been examined
for use in this amidation [Scheme 1(A)].10 However, the di-
rect ortho C−H amination of benzaldehydes remains chal-
lenging because of the weak coordinating ability and insta-
AgSbF6 (5 mol%)
RSO2N3
+
TDG (10 mol%)
DCE, 80 °C, 12 h
TDG = 3-trifluoromethylaniline (T3) or
2-amino-4-(trifluoromethyl)benzoic acid (T10) (10 mol%)
C) This work
Scheme 1 Metal-catalyzed ortho C(sp2)–H amination with organic
azides
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

B
O. K. Rasheed, F.-l. Zhang
Letter
Synlett
On the basis of previous observations,12,13,15 we com-
menced our studies by treating 2-methylbenzaldehyde
with tosyl azide under reported amidation conditions by
using 5 mol% of [Ru(p-cymene)Cl2]2, 16 mol% of AgNTf2, 30
mol% of AgTFA, and 10 mol% of the aniline derivative in 1,2-
dichloroethane (DCE) as solvent at 80 °C. We were pleased
to note that in a trial experiment, the desired C–H amidated
product was obtained in 30% NMR yield. Analysis of the 1H
NMR spectrum of the crude reaction mixture provided a
baseline value for the catalytic activity of ruthenium cata-
lyst in ortho C(sp2)–H amidation of benzaldehydes with or-
ganic azides. In an exploratory investigation, after extensive
screening, and from our previous studies on C–H activation
of benzaldehydes by the TDG strategy,15 we established that
anilines can serve as effective TDGs for Ru-catalyzed amida-
tion reactions with tosyl azide.
Control experiments showed that none of the desired
product was obtained in the absence of a TDG. For example,
when 2-methylbenzaldehyde was treated with tosyl azide
under the reported conditions {[Ru(p-cymene)Cl2]2, (2
mol%), AgSbF6 (0.3 equiv.), DCE, 80 °C, 12 h}9b in the ab-
sence of a TDG, none of the desired product was obtained.
Solvent screening was also an important step in optimizing
the reaction conditions; DCE, ethanol, and, in some cases,
isopropyl alcohol proved to be the best solvents; other sol-
vents tested gave significantly lower yields (see Supple-
mentary Information).
Next, we examined the role of additives in this type of
reaction. Interestingly, by addition of AgSbF6 instead of
AgNTf2, the yield of the C–H amidation reactions was sig-
nificantly improved and, in this reaction, AgSbF6 proved to
be the best chloride scavenger for generating active ruthe-
nium species. Ag2CO3 and AgTFA showed little reactivity in
the amidation reaction (see Supplementary Information).
With these optimized reaction conditions in hand, we
next explored the generality of this ruthenium-catalyzed
system by studying the substrate scope of various benz-
After extensive ligand screening (Scheme 2), T3 and T10
proved to be the most efficient TDGs, giving 95% and 96%
isolated yields, respectively, of the amidated product.
CHO
CHO
[Ru(p-cymene)Cl2]2 (3 mol%)
H
AgSbF6 (5 mol%)
NHTs
TsN3
+
TDG (10 mol%)
CHO
CHO
[Ru(p-cymene)Cl2]2 (3 mol%)
DCE, 80 °C, 12 h
1
2
3
H
AgSbF6 (5 mol%)
NHR
RN3
+
T3 or T10 (10 mol%)
R
NH2
R
NH2
O
NH2
NH2
DCE/EtOH, 80°C, 12 h
OH
COOH
H2N
CHO
Br
CHO
CHO
CHO
40%
CF3
NH2
NHTs
NHTs
X
NHTs
F3C
NHTs
85%a
40%
95%a
60%
T1
T4
T5
T2
T3
4
NH2
3
NH2
NH2
5
T3 X = a) F (88%);b) Cl (83%);
c) Br (85%);d) I (81%)
T10 X = a) F (85%); b) Cl (86%);
c) Br (83%);d) I (82%)
7
T3 95%
T10 96%
CF3
T3 51%
T10 55%
T3 94%
T10 92%
H3CO
CF3
CF3
F3C
CF3
60%
CHO
H
20%
T9
CHO
H
30%
55%
N
N
T6
T7
T8
S
S
CHO
O2
O2
NH2
NH2
NH2
CHO
NHTs
H
NH2
Cl
Br
F
F
F
F
8
N
10
S
MeO
COOH
T3 81%
T10 87%
O2
T3 84%
T10 81%
CF3
O
9
F3C
NO2
20%
T13
CF3
6
T3 88%
T10 92%
96%a,b
T3 64%
T10 59%
20%
10%
T12
CHO
NHTs
T11
T10
CHO
CHO
H
H
N
N
Scheme 2 Screening of TDGs for ortho C–H amidation of 2-methyl-
S
S
O2
benzaldehyde with tosyl azide. Yields are based on 1H NMR analysis ex-
cept where otherwise stated.
O2
12
a Isolated yield
11
b EtOH was used instead of DCE.
T3 71%
T10 73%
T3 47%
T10 44%
MeO
O
13
T3 70%
T10 67%
Next, we decided to optimize the reaction conditions to
improve the yield of the amidated product by using 3 mol%
of [Ru(p-cymene)Cl2]2 and 5 mol% of AgSbF6 with 10 mol%
of the aniline derivative as a TDG in DCE as solvent at 80 °C.
Scheme 3 Substrate scope of the Ru-catalyzed ortho C–H amination of
benzaldehydes with organic azides under the optimized reaction condi-
tions
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

C
O. K. Rasheed, F.-l. Zhang
Letter
Synlett
O
H
O
H
H
R
R
NHSO2R
-Ar-NH2
Ar-NH2
[Ru(p-cymene)Cl2]2
Ar
Ar
AgSbF6
N
-AgCl
N
H
R
R
NHSO2R
[Ru(p-cymene)](SbF6)2
14
15
H+
H+
Ar
N
-
SbF6
R
Ru
L
(p-cymene)
Ar
N
-
A
SbF6
R
Ru
N
(p-cymene)
O
S
R
O
E
N2
Ar
N
-
SbF6
R
Ar
Ru
N
-
(p-cymene)
SbF6
L
R
Ar
-
SbF6
N
Ru
R
(p-cymene)
B
N
Ru
S
R
O
(p-cymene)
O
N
O
N
O
N
R
S N3
S
R
O
D
O
C
Scheme 4 Proposed reaction pathway
aldehydes with tosyl azide (Scheme 3). The amidation of
benzaldehydes with electron-donating or electron-with-
drawing substituents proceeded well to provide the corre-
sponding products in good to excellent yields (40–95%)
with either TDG under the optimized reaction condition.16
Furthermore, the reaction of 2-methylbenzaldehyde with
various arylsulfonyl azides or alkylsulfonyl azides under the
optimized reaction conditions gave the desired amidation
products in good to excellent yields.
On the basis of the above experimental results and re-
ports in the literature,17,18 we propose the plausible reac-
tion mechanism shown in Scheme 4. First, treatment of
[Ru(p-cymene)Cl2]2 with AgSbF6 generates a cationic Ru
species that subsequently coordinates to substrate 14 to
form complex A. Chelation-assisted C–H metalation then
generates the ruthenacycle B. The azide coordinates to B to
form complex D with release of nitrogen gas, and complex
D then rearranges to afford the six-membered ruthenium
intermediate E. Finally, E undergoes reductive elimination
to form the final product.
In summary, we have developed a new protocol for the
Ru-catalyzed ortho C–H amidation of benzaldehydes with
organic azides by using a catalytic amount of TDG T3 or
T10. The reaction can be applied to a broad range of both
benzaldehydes and sulfonyl azides and it offers a conve-
nient method for the synthesis of various 2-(sulfonylami-
no)benzaldehydes in an economical manner without the
use of iridium.
Funding Information
O.K.R. and F.-l.Z. thank the Wuhan University of Technology for finan-
cial support. Also, O.K.R. thanks the University of Montana for sup-
port.
)(
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

D
O. K. Rasheed, F.-l. Zhang
Letter
Synlett
Acknowledgment
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dehyde: (a) Santhoshkumar, R.; Mannathan, S.; Cheng, C.-H.
J. Am. Chem. Soc. 2015, 137, 16116. (b) Lanke, V.; Prabhu, K. R.
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Tetrahedron Lett. 2005, 46, 2273.
(12) Zhang, Y.-F.; Wu, B.; Shi, Z.-J. Chem. Eur. J. 2016, 22, 17808.
(13) (a) Liu, X.-H.; Park, H.; Hu, J.-H.; Hu, Y.; Zhang, Q.-L.; Wang, B.-
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2017, 139, 888. (b) Hu, J.-H.; Xu, Y.-C.; Liu, D.-D.; Sun, B.; Yi, Y.;
Zhang, F.-L. RSC Adv. 2017, 7, 38077.
O.K.R. wishes to dedicate this report to the late Muhammad Rashid
Sheikh for his endless support.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591765.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
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(16) Ortho Amidation of Benzaldehydes with Organic Azides;
General Procedure
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A sealed tube equipped with a magnetic stirrer bar was charged
with the appropriate benzaldehyde derivatives (0.5 mmol, 1.0
equiv.), organic azide (1 mmol, 2.0 equiv.), [Ru(p-cymene)Cl2]2
(3 mol%), AgSbF6 (5 mol%), and T3 or T10 (10 mol%) at r.t. DCE or
EtOH (2 mL) was added, and the mixture was stirred at 80 °C for
12 h. When the reaction was complete, the mixture was cooled
to r.t., diluted with CH2Cl2, and filtered through a plug of silica
gel. The filtrate was concentrated in vacuo, and the resulting
residue was purified by flash chromatography [silica gel,
hexane–EtOAc (4:1)].
N-(2-Formyl-3-methylphenyl)-4-methylbenzenesulfon-
amide (3)
White solid; yield: 57.1 mg (96%); mp 95–97 °C. 1H NMR (400
MHz, CDCl3): δ = 2.36 (s, 3 H), 2.57 (s, 3 H), 6.85 (d, J = 7.4 Hz, 1
H), 7.23 (d, J = 8.1 Hz, 2 H), 7.35–7.49 (m, 2 H), 7.75 (d, J = 8.1 Hz,
2 H), 10.32 (s, 1 H), 11.42 (s, 1 H). 13C NMR (100 MHz, CDCl3):
δ = 19.0, 21.5, 116.1, 119.2, 125.6, 127.3, 129.8, 136.1, 136.5,
140.9, 143.8, 144.2, 194.0. MS (ES+): m/z = 290 [M + H]+. HRMS
(ES+): m/z [M + H]+ calcd for C15H16NO3S: 290.0845; found:
290.0849.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D