Manganese-Catalyzed ortho-C-H Amidation of Weakly Coordinating Aromatic Ketones

Article abstract of DOI:10.1021/acs.orglett.8b01770

An efficient manganese-catalyzed ortho-C-H amidation of weakly coordinating aromatic ketones using the readily available sulfonyl azide as the amination reagent is developed. The key step is the ketone directed aromatic metalation using the in situ generated reactive Mn intermediate, MnMe(CO)₅. This method offers excellent chemical yields, high regioselectivities, and good functional group tolerance.

Full text of DOI:10.1021/acs.orglett.8b01770

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Manganese-Catalyzed ortho-C‑H Amidation of Weakly Coordinating
Aromatic Ketones
Xianqiang Kong and Bo Xu*
College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Lu,
Shanghai 201620, China
S
* Supporting Information
ABSTRACT: An efficient manganese-catalyzed ortho-C-H amidation of
weakly coordinating aromatic ketones using the readily available sulfonyl
azide as the amination reagent is developed. The key step is the ketone
directed aromatic metalation using the in situ generated reactive Mn inter-
mediate, MnMe(CO)5. This method offers excellent chemical yields, high
regioselectivities, and good functional group tolerance.
romatic ketones are among the most important targets in
materials, pharmaceuticals, and other fine chemicals.
Scheme 1. Selected Examples of Mn-Catalyzed C−H
A
Amidations
Aromatic ketones are also commonly used as building blocks
in organic synthesis. Transitional metals, especially late tran-
sition metals such as Rh,1 Pd,2 Ir,3 and Ru4 catalyzed C−H
functionalizations, have evolved as atom- and step-economic
synthetic tools. Along this line, the ketone directed C−H func-
tionalization of aromatic ketones offers a straightforward and
efficient protocol for synthesis of highly functionalized ketones.
Indeed, since Murai and co-workers’ pioneering works on the
Ru-catalyzed aromatic C−H alkylation,5 the ketone directed
C−H activations have attracted much attention.6 However,
most of these reactions have relied heavily on precious late trans-
ition metals such as Ru, Rh, Pd, and Ir.6 More specifically, due to
the importance of aromatic amines in materials and phar-
maceuticals,7 direct ketone-directed C−H amidations have
attracted much attention (Scheme 1).8 For example, Liu and
co-workers reported a palladium-catalyzed ketone directed
C−H amidation of aromatic ketones (Scheme 1, eq 1).9 Using
organo azides as amination reagents,10 Sahoo and co-workers
reported a Ru(II)-catalyzed amidation of aromatic ketones
(Scheme 1, eq 2).11 Chang and co-workers also reported
iridium-catalyzed (Scheme 1, eq 3)3c C−H amidations and
ruthenium-catalyzed (Scheme 1, eq 4)12 C−H amidation. Very
recently, Rasheed and co-workers reported a Ru-catalyzed C−H
amination of aromatic aldehyde (Scheme 1, eq 5).13
highly efficient manganese-catalyzed ortho-C-H amidation of
weakly coordinating aromatic ketones by using the readily
available sulfonyl azides as amidation reagents.
We used the amidation of acetophenone 1a as our model
reaction (Table 1). Using MnBr(CO)5 as catalyst, the standard
condition used by Wang and co-workers (MnBr(CO)5/ZnBr2/
Me2Zn)18 did not give any product (Table 1, entry 1). We
thought the Lewis acid used, ZnBr2, may not be strong enough
to activate the relatively weak electrophile−sulfonyl azide 2a.
Thus, we screened many Lewis acidic activators, especially Lewis
acids, which were known to be good activators for organoazides
(e.g., silver and copper Lewis acids)19 (Table 1, entries 2−7).
Because of the weak coordinating power of ketone groups and
the lower catalytic reactivity of base metals (such as iron,14
cobalt,15 copper,2e,16 and manganese17) compared with the late
transition metals, the use of base metal catalysts in the ketone-
directed C−H activations is challenging. To the best of our
knowledge, base metal catalyzed C−H amidation of weakly
coordinating aromatic ketones has not been achieved. Recently,
Wang and co-workers reported a manganese-catalyzed aromatic
C−H addition of aromatic ketones to imines using the in situ
generated reactive Mn specie, MnMe(CO)5.18 We envisioned
that a similar strategy could be used in base metal catalyzed
ketone-directed C−H amidation. Herein, we are glad to report a
Received: June 9, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01770
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Conditions
Scheme 2. Scope for Manganese-Catalyzed Amidation of
a
Aromatic Ketones
a
Conditions: 1a (0.2 mmol), 2a (0.3 mmol), MnBr(CO)5 (5 mol %),
Lewis acid, additive, solvent (1 mL), 6 h.
To our delight, the Cu(OAc)2 system gave a small amount of
product 3a (Table 1, entry 7). We investigated the solvent effect
(Table 1, entries 8−13). The solvent had a big influence on the
reaction: most solvents only gave a trace amount of product 3a
and only dioxane offered moderate conversion (Table 1, entry 9).
We then screened combinations of Cu(OAc)2 equivalents and
Me2Zn equivalents (Table 1, entries 14−18). To our delight,
when 1.5 equiv of Cu(OAc)2 and 2.0 equiv of Me2Zn were used,
73% yield of product 3a was obtained (Table 1, entry 17). In the
last, we found that the chemical yield could be further improved
by increasing the reaction temperature from 60 to 80 °C (Table 1,
entry 19). However, further increasing reaction temperature to
90 °C had a deleterious effect (Table 1, entry 20).
With the optimized conditions in hand, we explored the
substrate scope and functional group tolerance for the
manganese-catalyzed amidation of aromatic ketones. First, we
evaluated the scope of aromatic ketones by reactions with
phenylsulfonyl azide 2a (Scheme 2). The substitution pattern
(meta, para) and electronic properties of substitution (electron
deficient or rich) on the aromatic ring of ketone 2 played a small
role; good yields were obtained regardless (3a−3s) (Scheme 2).
Various functional groups such as halides (3b, 3c, 3g, 3k)
(Scheme 2), nitro group (3f) (Scheme 2), ethers (3h, 3l)
(Scheme 2), ester (3i) (Scheme 2), ketone (3r) (Scheme 2),
alkyl groups (3d, 3j) (Scheme 2), and trifluoromethyl group (3e)
(Scheme 2) were well tolerated. This reaction also worked
equally well for a ketone with a long aliphatic chain (3m)
(Scheme 2) and cyclic ketones (3n−3q) (Scheme 2). Our
method also worked well for amidation of fused aromatic ketone
such as 1-naphthalenyl ketone (3s) (Scheme 2). When diaryl
ketone was used, higher a temperature (120 °C) and longer
reaction time were needed (3t, 3u) (Scheme 2). For reaction of
unsymmetrical diarylketone, a mixture of inseparable regioiso-
meric mixture was obtained (3u, 3u′) (Scheme 2). We also
tested reactions of aromatic compounds such as benzaldehydes,
benzamides, methyl benzoate, and azobenzol using standard
conditions, and no amidation product was obtained.
a
Conditions: 1 (0.2 mmol), sulfonyl azide 2 (0.3 mmol), MnBr(CO)5
(5 mol %), Cu(AcO)2 (0.3 mmol), dioxane (1.0 mL), and Me2Zn
(1.2 M in toluene, 0.4 mmol), 80 °C, 6 h. (b) 120 °C, 36 h.
Then we explored the amidation of acetophenone 1a with
various aromatic and aliphatic sulfonyl azides 2 (Scheme 3).
Good yields of amidation products were obtained in general.
Various functional groups such as amine (3v) (Scheme 3),
trifluoromethyl (3ad, 3af) (Scheme 3), ether (3z) (Scheme 3),
halides (3w, 3ac, 3ae, 3ag, 3ah) (Scheme 3), and ester (3y)
(Scheme 3) were well tolerated. This reaction also worked
equally well for aliphatic sulfonyl azides 2 (3ai, 3aj, 3ak)
(Scheme 3). It should be noted that no reaction took place when
a highly bulky sulfonyl azide was used (3al) (Scheme 3).
To elucidate the effect of electronic factor on the rate of
manganese-catalyzed ortho-C-H amidation, we conducted a
competition experiment (Scheme 4, eq 1). An electron-donating
group (−OMe) enhanced the amination compared to electron-
withdrawing group (−COOMe) but in a small margin (2:1).
Also, our methodology can be used in larger scale synthesis
without complications (Scheme 4, eq 2).
The proposed mechanism is illustrated in Scheme 5 based
on precedent reports.17,18,20 The catalytic cycle starts with the
generation of MnMe(CO)5 from transmetalation of MnBr(CO)5
with Me2Zn by releasing methane gas.21 Then complexation of
B
DOI: 10.1021/acs.orglett.8b01770
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
MnMe(CO)5 with acetophenone 1a gives intermediate A. Then
aromatic metalation of A gives manganacycle intermedi-
ate B.21 A reversible coordination of tosylazide to the cationic
Mn center and then an amido insertion leads to Mn-intermediate
C by releasing a nitrogen molecule. Because Cu(OAc)2 is a strong
oxidant, it could be reduced by Et2Zn to give Cu(I) species22
(represented as [Cu]), which may be able to activate azides 2.
In the last, the transmetalation of C with Me2Zn affords inter-
mediate D, which undergoes a ligand exchange with 1a to repro-
duce intermediate A and also generates the copper containing
intermediate E. At last, the workup of E gives the final product 3a.
In summary, we have developed an efficient amidation of
various aromatic ketones via C−H bond activation using readily
available sulfonyl azides catalyzed by a base metal catalyst,
MnBr(CO)5. At present, MnBr(CO)5 is still relatively expen-
sive, use of cheaper manganese sources in C−H activations is
currently being investigated in our laboratories.
Scheme 3. Scope for Sulfonyl Azides 2
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b01770.
Experimental details and copies of NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: bo.xu@dhu.edu.cn.
ORCID
a
Conditions: 1 (0.2 mmol), sulfonyl azide 2 (0.3 mmol), MnBr(CO)5
(5 mol %), Cu(AcO)2 (0.3 mmol), dioxane (1.0 mL), and Me2Zn
(1.2 M in toluene, 0.4 mmol), 80 °C, 6 h.
Bo Xu: 0000-0001-8702-1872
Notes
The authors declare no competing financial interest.
Scheme 4. Mechanistic Study and Larger Scale Synthesis
ACKNOWLEDGMENTS
We are grateful to the National Science Foundation of China for
financial support (NSFC-21472018 and NSFC-21672035).
■
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