Rh(III)-Catalyzed Regioselective Acetylation of sp2 C?H Bond Starting from Paraformaldehyde

Article abstract of DOI:10.1002/cctc.201801512

Rh(III)-catalyzed acetylation of sp² C?H bonds has been realized using paraformaldehyde as an acetylating reagent. This procedure features simultaneous formation of two C?C bonds, external oxidants free, and water as the sole byproducts, thus offering an environmentally benign acetylation of arenes. A range of functional groups tolerance were observed.

Full text of DOI:10.1002/cctc.201801512

Accepted Article
Title: Rh(III)-Catalyzed Regioselective Acetylation of sp2 C-H Bond
Starting from Paraformaldehyde
Authors: Ting Wan, Sidong Du, Chao Pi, Yong Wang, Rongbin Li,
Yangjie Wu, and Xiuling Cui
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10.1002/cctc.201801512
ChemCatChem
COMMUNICATION
Rh(III)-Catalyzed Regioselective Acetylation of sp2 C-H Bond
Starting from Paraformaldehyde
Ting Wan, Sidong Du, Chao Pi*, Yong Wang, Rongbin Li, Yangjie Wu and Xiuling Cui* [a]
Abstract: Rh(III)-catalyzed acetylation of sp2 C-H bonds has been
realized using paraformaldehyde as an acetylating reagent. This
procedure features simultaneous formation of two C-C bonds,
external oxidants free, and water as the sole byproducts, thus
offering an environmentally benign acetylation of arenes. A range of
functional groups tolerance were observed.
The acetyl (-COCH3) group is a prominent and versatile
functional group in organic synthesis, which can be converted to
alcohols, imines, oximes, and other functional groups.[1]
Moreover, it also plays an important role in synthesis of
heterocycles.[2] Conventionally, the acetylation of arenes
strongly relies on Friedel–Crafts reactions, which suffer from the
limitation of electron-rich arenes, poor regioselectivity and
requirement of excessive Lewis acids.[3] To settle these
problems, transition metal-catalyzed acetylation of C(sp2)−H
bonds starting from acetaldehyde, butanedione, acetate,
crotonic acid, acetonitrile, and 2-butyne via C-H,[4] C-C,[5] C-O[6]
C=C,[7] C≡N[8] and C≡C[9] bond cleavage has been extensively
investigated based on the great progress of transition metal-
catalyzed C−H activation over the past decade.[10] For instance,
Scheme 1. Previous work and this work.
Wang and coworkers[5a] developed a palladium-catalyzed direct
acetylation of arylpyridines with diketobutane as an acetyl
reagent in the presence of TBHP in 2012. Subsequently, Wang
hydroxymethylation of arenes via a migration insertion of
group[8c] disclosed an acetylation of arenes by a manganese-
paraformaldehyde (Scheme 1b). Rh(III)-catalyzed C−H
catalyzed C−H activation and synergetic utilization of Me2Zn and
functionalization of arenes has attracted considerable attention
ZnBr2. In 2016, Xie[9] described a Rh-Cu bimetallic catalyzed o-
because of the versatility, high reactivity, stability, and wide use
acetylation of acyloxacetamide with 2-butyne (Scheme 1a).
of rhodium catalysts in chemistry.[16] To the best of our
On the other hand, paraformaldehyde[11] as being cheap,
knowledge, there is no report on paraformaldehyde as the acetyl
stable, low toxicity and simple to operate has been used as a C1
synthon through Rh,[12] Pd,[13] Co-catalyzed[14] direct C–H
functionalization. For instance, Chatani group[12b] reported a
Rh(I)-catalyzed synthesis of indenone starting from alkynes with
2-bromophenylboronic acids and using paramaldehyde as
carbonyl source. In 2014, Beller and coworkers[13b] developed a
protocol for palladium-catalyzed carbonylation of aryl bromides
using paraformaldehyde as an external CO source. In addition,
Ding[15] group disclosed Ru(II)-catalyzed regioselective direct
source to build acetyl group. Herein we disclose a Rh(III)-
catalyzed regioselective acetylation of arenes using
paraformaldehyde as a novel acetyl reagent and internal oxidant
via C−H activation. This procedure avoided external oxidants
and underwent twice insertion of aldehyde, forming two C-C
bonds (Scheme 1c).
We initiated our study on the model reaction of 2-
phenylpyridine 1a and paraformaldehyde 2 in the presence of 5
mol% of [Cp*RhCl2]2 and 20 mol% of AgOAc in TFE (2,2,2-
Trifluoroethanol) at 120 oC for 24 h (Table 1, Entry 1). An oil
product was isolated in 45% yield, and identified as its structure
to be 1-(2-(pyridin-2-yl)phenyl)ethanone 3a by NMR and HRMS
spectra. TFE was proved to be the optimal solvent and other
solvents, such as DCE (1,2-Dichloroethane), acetone, MeOH,
THF (Tetrahydrofuran) (Entries 2−5), completely suppressed the
reactivity and no product was observed. The evaluation of
additives suggest that AcOH was effective in this transformation
(Entries 6−9). This reaction smoothly proceeded in the presence
of AcOH (1 equiv), providing 3a in significantly improved yield
(93%), as shown in entry 9. Moreover, the reaction temperature
[a]
T. Wan, S. Du, Dr. C. Pi, Y. Wang, R. Li, Prof. Y. Wu, Prof. X. Cui
College of Chemistry and Molecular Engineering
Zhengzhou University
75 Daxue Street, Zhengzhou, Henan Province 450052, China
E-mail: cuixl@zzu.edu.cn; pichao@zzu.edu.cn
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Table 1. Optimization of various parameters for the reaction of 2-
phenylpyridine 1a with paraformaldehyde 2.[a]
Table 2. Scope of substrates 1.[a]
Entry
Silver salt
Solvent
Additive
Yield[b] (%)
1
2
3
4
5
6
7
8
9
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgNTf2
AgSbF6
AgBF4
AgNTf2
AgNTf2
/
TFE
DCE
Acetone
MeOH
THF
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
/
/
/
/
45
ND
ND
ND
ND
74
52
75
93
81
85
95
89
40
ND
ND
63
/
CsOAc
NaOAc
PivOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
10[c]
11[d]
12
13
14
15[e]
16[f]
17
18[g]
AgNTf2
93
[a] Reaction conditions: 1a (0.1 mmol), 2 (6 equiv), catalyst (5 mol%), silver
salt (20 mol%), additive (1.0 equiv), solvent (2 mL), 120 oC, 24 h. [b] Isolated
yield. [c] Additive (0.5 equiv). [d] 100 oC. [e] Without 2. [f] Without catalyst.
[g] Under N2. [h] ND = not detected.
was decreased to 100 °C (Entry 11). Further screening silver
salts (Entries 12-14) revealed that AgNTf2 was proved to be
beneficial, affording product 3a in 95% yield (Entry 12). In order
to verify the role of the 2, the reaction was carried out in the
absence of 2 under the same reaction conditions. No reaction
occurred (Entry 15). In addition, no product was observed in the
absence of [Cp*RhCl2]2. The desired product was obtained in
63% yield detected in the absence of silver salt (Entry 17). 3a
was observed when the reaction was performed under N2 (Entry
18), which indicated the external oxidants could be avoided.
With the optimal reaction conditions in hand, we embarked
on the substrate scope via running the reactions in TFE at 120
oC for 24 h under air atmosphere using 5 mol% [Cp*RhCl2]2 and
20 mol% AgNTf2 as catalyst, 1 equiv AcOH as additive. A wide
range of 2-phenylpyridines underwent acetylation efficiently in
spite of the electronic and steric effects from the substituents
(Table 2). Electron-donating (-Me, -OMe) and withdrawing (-F, -
Cl, -Br, -CF3) groups at para-position on the phenyl ring were
readily coupled with paraformaldehyde to provide the
corresponding products in 57%-99% yields (3a-3g). The reaction
[a] Reaction conditions: 1a (0.1 mmol), 2 (6 equiv), [Cp*RhCl2]2 (5
mol%), AgNTf2 (20 mol%), AcOH (1.0 equiv), TFE (2 mL), 120 oC, 24 h.
functional groups, such as CH3 (3k), F (3l), Cl (3m), Br (3n), CF3
(3o), OMe (3p), COOMe (3q). Additionally, 2-(2,3-
dihydrobenzo[b][1,4]dioxin-5-yl)pyridine
and
4-methyl-2-
phenylpyridine with 2 supplied the corresponding products (3r,
3v) in 48% and 99% yields, respectively. In particular, the
reactions showed good reactivity with a methyl, methoxy and
fluorine groups at the o-position of the phenyl ring (3s–3u), thus
showing tolerance of steric hindrance. 1-(2-(Isoquinolin-1-
yl)phenyl)ethan-1-one (3w) was found to be useful in this
transformation. Unfortunately, the reaction is not suitable for
benzaldehyde and acetaldehyde.
of 2-((1,1’-biphenyl)-4-yl)-pyridine 1h with
2 provided the
corresponding product 3h in 93% yield. We were delighted to
find that the reaction of 2-phenylpyridine with challenging groups
(–COOMe and –COMe) also proceeded well (3i, 3j). The
molecular structure of 3i was confirmed by X-ray single crystal
diffraction analysis (see the SI). These results indicated that the
electron density of benzene did not significantly affect this
transformation. The meta-substituted substrates showed
excellent compatibility with various
To further illustrate the synthetic utility of this direct C-H
acetylation, the transformations of the product 3a were
performed. As depicted in Scheme 2, the product 3a could be
easily converted to compound 5[1a] and oxime 6[1d] (Scheme 2a).
The α,β- unsaturated ketones are versatile synthetic
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intermediates, which can be provided by aldol condensation of
[d5]pyridine (1a-d5) with 2, hydrogen of acetyl group was
deuterium in 40%-D (eq 3). When 2-phenyl-[d5]pyridine (1a-d5)
reacted with 2 in AcOD and TFE-d3, hydrogen of acetyl group
was deuterium in 84%-D (eq 4). We observed 81%-D in acetyl
group and 80%-D in o-position of the phenyl ring when 3a was
treated in TFE-d3 with catalyst in the absence of
paraformaldehyde (eq 5). Those results indicated that hydrogen
of acetyl group could come from benzene ring of 1a and
underwent rapid H/D exchange with TFE. The observed KIE
value of 2-phenylpyridine (1a) and 2-phenyl-[d5]pyridine (1a-d5)
(1:1 in molar ratio) is 1.0, revealing the cleavage of the C(sp2)-H
bond might not be involved in the rate-determining step (eq 6).
3a and aldehyde in Scheme 2b. [17]
Based on the preliminary mechanistic experiments and
[15,18]
literature reported,
a plausible reaction mechanism is
Scheme 2. Synthetic application of the product 3a
.
proposed in Scheme 4. First, the coordination of 1a with the
active RhIII catalyst triggers ortho C-H bond cleavage to give the
five-membered metallocycle B. Then, migratory insertion of
aldehyde into B forms the seven-membered rhodacycle D,
which undergoes 1.2-hydrogen migration to give transition state
E. [19] Then migratory insertion of aldehyde into E delivers the G.
Subsequent beta-OH elimination forms intermediate H[20] as well
as active RhIII catalyst for the next catalytic cycle. Finally, the
final product 3a was obtained through isomerism of H.
Scheme 4. Plausible mechanism.
In summary, we have first reported an efficiently
regioselective Rh-catalyzed acetylation of arenes using
paraformaldehyde as an acetylated reagent, which may undergo
twice the insertion of aldehyde forming two C-C bonds in one-
pot. This protocol was carried out under air and avoided external
oxidants, offering an environmentally benign method to
synthesize acetylated arenes.
Scheme 3. Mechanistic studies.
To gain further insight into the reaction mechanism, a series
of control experiments were conducted (Scheme 3). First, the
condensation of 2-phenylpyridine 1a with 13C-labelled
paraformaldehyde 2’ under the standard reaction conditions
afforded the 13C-labelled products 3a’, which indicated that
paraformaldehyde worked as an acetyl reagent (eq 1). Changing
the solvent from TFE to TFE-d3, hydrogen of acetyl group was
deuterium in 37%-D (eq 2). Then the reaction of 2-phenyl-
Experimental Section
To a 25 mL flame-dried tube was added [Cp*RhCl2]2 (5.0 mol%), AgNTf2
(20 mol%) TFE (2.0 mL), 2-phenylpyridines (0.1 mmol),
paraformaldehyde (0.6 mmol) and AcOH (1 equiv). The tube was sealed
and stirred at 120 oC for 24 h. When the reaction was completed, the
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10.1002/cctc.201801512
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COMMUNICATION
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Entry for the Table of Contents
COMMUNICATION
Ting Wan, Sidong Du, Chao Pi*, Yong
Wang, Rongbin Li, Yangjie Wu and
Xiuling Cui*
Page No. – Page No.
Rh(III)-Catalyzed Regioselective
Acetylation of sp2 C-H Bond Starting
from Paraformaldehyde
Rh(III)-catalyzed regioselective acetylation of arenes using paraformaldehyde as a
novel acetyl reagent, which may undergo twice insertion of aldehyde and form two
C-C bonds in one-pot manner. This protocol proceeded smoothly under air atmos-
phere, avoided external oxidants, and produced water as the sole byproduct.
This article is protected by copyright. All rights reserved.