Iridium-Catalyzed Direct ortho-C-H Amidation of Benzaldehydes through N-Sulfonyl Imines as Mask

Article abstract of DOI:10.1021/acs.orglett.6b02406

Ir-catalyzed direct C-H sulfamidation of benzaldehydes has been achieved. A series of ortho-amided benzaldehydes were obtained in up to 95% yields for 21 examples with excellent regioselectivity and broad functional group tolerance. This transformation could proceed smoothly with low catalyst loading under external-oxidant-, acid-, or base-free conditions. Molecular nitrogen was released as the sole byproduct, providing an environmentally benign sulfamidation process.

Full text of DOI:10.1021/acs.orglett.6b02406

Letter
pubs.acs.org/OrgLett
Iridium-Catalyzed Direct ortho-C−H Amidation of Benzaldehydes
through N‑Sulfonyl Imines as Mask
Yudong Li, Yadong Feng, Linhua Xu, Lianhui Wang, and Xiuling Cui*
Engineering Research Center of Molecular Medicine of Ministry of Education, Key Laboratory of Fujian Molecular Medicine,
Key Laboratory of Xiamen Marine and Gene Drugs, School of Biomedical Sciences, Huaqiao University, Xiamen 361021, P. R. China
S
* Supporting Information
ABSTRACT: Ir-catalyzed direct C−H sulfamidation of
benzaldehydes has been achieved. A series of ortho-amided
benzaldehydes were obtained in up to 95% yields for 21
examples with excellent regioselectivity and broad functional
group tolerance. This transformation could proceed smoothly
with low catalyst loading under external-oxidant-, acid-, or
base-free conditions. Molecular nitrogen was released as the
sole byproduct, providing an environmentally benign sulfamidation process.
Scheme 1. Transition-Metal-Catalyzed C−H Amination
irect functionalization of C−H bonds has emerged as a
from Organic Azides
D
powerful tool in organic synthesis to provide complex
molecules from easily available starting materials and improve
the overall efficiency of the desired transformation. In the past
decade, great progress has been achieved in transition-metal-
catalyzed C−H bond functionalizations.1 Controlling site
selectivity is one of the challenges. In this regard, the strategy
involving regioselective C−H activation assisted by various
directing groups shows high potential. Various directing groups
have successfully been utilized for regioselective C−H function-
alization. So far, directing groups containing oxygen or nitrogen
atoms, such as carboxylic acid,2 ketone carbonyl,3 phenolic
hydroxyl,4 imine,5 oxime,6 benzamide,7 benzhydroxamic acid,8
hydroxamic acid,9 amide,10 acetanilide,11 acrylamide,12 enam-
ine,13 urea,14 azide,15 and some heterocycles16 including azole,
imidazole, benzimidazole, benzoxazole, indole, and pyridine
have been developed. However, aldehyde as a directing group
remains challenging17 because of the low ligating ability of
the aldehyde oxygen and related competitive side reactions. In
addition, aldimine offers stronger chelation assistance for C−H
activation and acts as a surrogate of aldehydes.18 On the other
hand, organic azide, as an internal oxidant and environmentally
benign reagent, is widely developed by Sukbok Chang and
other groups because nontoxic nitrogen gas is released as the
only byproduct.19 Herein, we disclose an Ir-catalyzed amidation
of benzaldehydes with sulfonyl azides as amino sources and
N-Ts imines as a removable directing group (Scheme 1b). This
procedure could proceeded smoothly with a low catalyst
loading and tolerate various substituent groups. The products
are an important building block in organic synthesis and can
be easily converted into various highly valuable molecules via
diverse transformations.20
1,2-DCE using AgSbF6 as an additive after 12 h at 100 °C (entry 1).
The reaction did not work well in the absence of a AgSbF6 or an
Ir(III) catalyst (entries 2−3). Various additives, such as AgOAc,
AgBF4, AgNTf2, were further screened, and it was found that
AgNTf2 could evidently promote this amidation and give the
desired product 3aa in 89% yield (entries 4−6). With such an
exciting preliminary result in hand, a systematic screening solvent
was carried out (entries 6−9). 1,2-DCE proved to be optimal.
In view of the fact that high temperature might lead to
decomposition of the product, the reaction temperature was
decreased from 100 to 40 °C. A similar result could be main-
tained at 60 °C (entry 11). When loading of the catalyst was
reduced to 0.5 mol %, a slightly lower yield was obtained
(entry 13). While, no conversion was observed using [RhCp*Cl2]2,
[Ru(p-cymene)Cl2]2, or Pd(OAc)2 as a catalyst (entries 14−16).
At the outset of our studies, the reaction of N-Ts benzal-
dehyde imine (1a) and para-toluenesulfonyl azide (2a) was
chosen as a model reaction to screen various reaction param-
eters (Table 1). To our great delight, the desired product 3aa was
isolated in 68% yield in the presence of [IrCp*Cl2]2 (1 mol %) in
Received: August 11, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02406
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
entry
catalyst
[IrCp*Cl2]2
silver salt
solvent
DCE
t (°C)
3aa (%)
1
AgSbF6
AgSbF6
none
100
100
100
100
100
100
100
100
100
80
68
2
none
DCE
N.R.
N.R.
50
3
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[RhCp*Cl2]2
Pd(OAc)2
DCE
4
AgOAc
AgBF4
DCE
5
DCE
43
6
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
DCE
89
7
DMF
DMSO
1,4-dioxane
DCE
N.R.
N.R.
40
8
9
10
11
12
89
DCE
60
89
DCE
4
73
b
13
DCE
60
76
14
15
16
DCE
60
N.R.
N.R.
N.R.
DCE
60
[Ru(p-cymene)Cl2]2
DCE
60
a
b
1a (0.2 mmol), 2a (0.24 mmol), [IrCp*Cl2]2 (1 mol %), AgNTf2 (8 mol %), solvent (2 mL), 12 h, isolated yields, under air. [IrCp*Cl2]2 (0.5 mol %),
AgNTf2 (4 mol %). DMF = N,N-dimethylformamide. DMSO = dimethyl sulfoxide.
a
With the optimal reaction conditions in hand, the scope of
sulfonyl azides 2 was then examined in the amidation of
4-methyl-N-[(2-methylphenyl)methylene]benzenesulfonamide
(Scheme 2). Aromatic rings substituted with electron-donating
and -withdrawing groups were readily sulfamidated at the ortho-
position and provided the desired products in good to excellent
yields (3aa−3af). The electron density of arensulfonyl azides
has a slight influence on this transformation. In addition broad
functional groups were also tolerated. For instance, arensulfonyl
azides bearing fluoro (3ae), chloro (3ac) groups were smoothly
sulfamidated in excellent yields. A 72% yield was obtained for
4-nitrobenzenesulfonylazide (3ad). Arylsulfonyl azide bearing a
chloro group at the meta-position could readily participate in
this sulfamidation reaction, providing product (3ah) in 75%
yield. A substituent at the ortho-position of the benzene ring
(3ag) led to a lower yield than the para-methylbenzenesulfonyl
azide (3aa) perhaps due to the steric hindrance. Moreover,
aliphatic sulfonyl azides also worked well. Ethylsulfonyl azide
afforded the corresponding product (3ai) in 95% yield.
Scheme 2. Substrate Scope
Next, we investigated various N-Ts benzaldehyde imines 1
with para-methyl henylsulfonyl azide under the optimized con-
ditions (Scheme 2). Ortho-sulfamidated products with electron-
donating substituents, such as methyl (3aa) or methoxyl (3da),
were obtained in 89% and 82% yields, respectively. In addition,
substrates bearing electron-withdrawing groups, such as fluoro
(3ba), bromo (3ca), or trifluoromethyl (3ea) groups, were
applied to this reaction system and gave the corresponding
products in good yields. For para-substituted imines, two C−H
bonds possibly could be aminated. Both mono- and diamidated
products could be afforded. In view of the steric effect of the
N-TS group, the hydroamidated products (3fa−3ia) could be
afforded in moderate yields after slightly modifying the reaction
conditions. In the case of meta-substituted imines, the C−H
activation occurred selectively and consistently at the less hin-
dered site (3ja). 2-Thienylaldehyde was successfully converted
to the corresponding product (3la) in 50% yield. Moreover,
4-methyl-N-(naphthalen-1-ylmethylene)-benzenesulfonyl amide
a
Reaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), [IrCp*Cl2]2
(1 mol %), AgNTf2 (8 mol %) in DCE (1.0 mL) at 60 °C for 12 h
under air. 1 (0.24 mmol), 2 (0.2 mmol), [IrCp*Cl2]2 (1.5. mol %),
AgNTf2 (12 mol %).
b
also proceeded well and provided the targeted compound in
85% yield (3ma). The amidated aldehydes are known as
B
DOI: 10.1021/acs.orglett.6b02406
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
important precursors for the synthesis of a variety of complex
structures. The preinstalled halogen, methoxy, and trifluor-
omethyl groups in the coupled products are typically encoun-
tered in organic synthesis and should allow further chemical
transformations.
We conducted parallel reactions of substrates 1k or [D5]-1k
with para-methyl phenylsulfonyl azide (2a) under the standard
reaction conditions. A significant kinetic isotope effect (kH/kD =
2.7) was found, suggesting the irreversible C−H cleavage to be
the rate-determining step (Scheme 3).21
are important building blocks in organic synthesis and could
be easily converted into various highly valuable molecules via
diverse transformations.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02406.
Experimental procedures, compound characterization
(PDF)
Scheme 3. Kinetic Isotope Effect Studies with Labeled
Compound [D5]-1k
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: cuixl@hqu.edu.cn.
Notes
The authors declare no competing financial interest.
According to the literature,19 a plausible reaction pathway for
this Ir(III)-catalyzed amidation reaction was proposed and is
shown in Scheme 4. Initially, the dimeric precursor [IrCp*Cl2]2
ACKNOWLEDGMENTS
■
This research was supported by NSF of China (21572072),
Xiamen Southern Oceanographic Center (15PYY052SF01),
Science and Technology Bureau of Xiamen City
(3502Z20150054), and Huaqiao University.
Scheme 4. Proposed Reaction Mechanism
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Org. Lett. XXXX, XXX, XXX−XXX