Carbonylative Acetylation of Heterocycles

Article abstract of DOI:10.1002/ejoc.201901728

Herein, a new procedure for the carbonylative acetylation of heterocycles has been developed. In this process, organic peroxide acts as the methyl source. Various heterocycles were transformed into the corresponding methyl heterocyclic ketones in moderate to good yields.

Full text of DOI:10.1002/ejoc.201901728

A Journal of
Accepted Article
Title: Carbonylative Acetylation of Heterocycles
Authors: Youcan Zhang, Zhiping Yin, and Xiao-Feng Wu
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901728
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10.1002/ejoc.201901728
European Journal of Organic Chemistry
COMMUNICATION
Carbonylative Acetylation of Heterocycles
Youcan Zhang+, Zhiping Yin+ and Xiao-Feng Wu*[a]
[a]
M. Sc. Y. Zhang, Dr. Z. Yin, Dr. habil. X.-F. Wu, Department Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Straße 29a,
18059 Rostock, Germany
E-mail: Xiao-Feng.Wu@catalysis.de
https://www.catalysis.de/mitarbeiter/wu-xiao-feng/
Supporting information for this article is given via a link at the end of the document.
+ Youcan Zhang and Zhiping Yin contributed equally to this work.
Abstract: Herein, a new procedure for the carbonylative acetylation
of heterocycles has been developed. In this process, organic
peroxide acts as the methyl source. Various heterocycles were
transformed into the corresponding methyl heterocyclic ketones in
moderate to good yields.
be easily captured by carbon radicals to form carbonyl radicals,
which can be introduced into organic compounds.[7] Additionally,
as an unique advantage, 13C labelled compounds can be easily
prepared by using [13C]CO gas.[8]
As our continues interests on developing new
carbonylation reactions,[9] we noticed the mentioned challenge
on acetylation of electron-deficient heterocycles. Taking the
advantage of one carbon chain prolongation in carbonylation
chemistry, only one methyl group is needed for the targeted
acetylation which can be obtained from dicumyl peroxide
(Scheme 1). With this hypothesis, we are potentially able to
develop a new carbonylative procedure for the acetylation of
heterocycles.
In order to realize this procedure, we selected 1-methyl-
1H-benzo[d]imidazole 1a as the model substrate, DCP as the
oxidant and methyl source to optimize the reaction conditions.
To our delight, the desired 1-(1-methyl-1H-benzo[d]imidazol-2-
yl)ethan-1-one 1aa can be obtained in 34% yield, when add 1.5
equivalents of DCP in DCE (1,2-dichloroethane) (1 mL) under
CO (20 bar) atmosphere at 120 °C (Table 1, entry 1). Then
different solvents such as 1,4-dioxane, DMF, PhCF3, PhCl , and
MeCN were tested and the desired product was all obtained in
decreased yields (Table 1, entries 2-6). The yield of the target
product can be further improved by raising the reaction
temperature to 130 °C and increasing CO pressure to 40 bar
(Table 1, entry 7). Next, we examined the influence of different
acids as additives in the acetylation, delightfully, when TFA and
AcOH were used as the additives, the yield of 1aa raised to 54%
and 53%, respectively (Table 1, entries 8-11). The loading of
AcOH was tested subsequently; a 66% yield of 1aa can be
obtained when adding 3 equivalents of AcOH into the reaction
mixture and raising the temperature to 140°C (Table 1, entries
12-14). The loading of DCP was tested as well, however, the
yield of 1aa decreased to 37% with 1 equivalent of DCP was
used, while increasing the amount of DCP could not further
improve the reaction outcome (Table 1, entries 15-16). Other
peroxides as a source of methyl were screened as well, such as
DTBP (di-tert-butyl peroxide) was less effective to afford the
desired product and TBHP (tert-butyl hydroperoxide solution,
70% in H2O) did not promote the desired transformation (Table 1,
entries 17-18). Satisfactorily, in the case of using a mixed
solvent of DCE and PhCl (1:1), the desired product 1aa was
formed in a 70% yield (Table 1, entry 19). Control experiments
revealed that no target product could be formed in the absence
of CO gas or DCP (Table 1, entries 20-21). Finally, the best
Nitrogen-containing heterocycles are an important class of
structural elements and are an integral parent of many
biologically active molecules, which have wide applications in
chemistry and biology.[1] In particular, acetyl heterocycles such
as 1-acetylisoquinolines,[2] 2-acetylbenzimidazoles[3] and 2-
acetylbenzothiazoles[4] are very useful intermediates and have
attracted widespread attention for the preparation of molecules
with pharmacological or biological activities from them. However,
compared with the acetylation of electron-rich aromatic
compounds (Friedel-Crafts reaction), it is still a challenge for
acetylation of electron-deficient heterocyclic compounds.
Traditionally, acetylation can be relatively realized with acetyl
chloride or acetic acid, but the selectivity and functional
tolerance of these methods usually problematic. Additionally, the
acetic acid and derivatives used are produced by Rh- or Ir-
catalyzed carbonylation of methanol. Alternatively, acetylation
were studied with acetaldehyde, pyruvic aldehyde, pyruvic acid
and many other acetylation agents as well.[5] Although they all
have their own advantages, new alternative procedures are still
under demand.
Scheme 1. Method design for carbonylative acetylation of
heterocycles.
On the other hand, carbonylation reactions are powerful
tools for introducing carbonyl group into C-X (X = I, Br, OTf, etc.)
bonds and has been widely applied in organic synthesis.[6]
Carbon monoxide as a cheap and accessible C1 source that can
1
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10.1002/ejoc.201901728
European Journal of Organic Chemistry
COMMUNICATION
results can be obtained in the presence of 1.5 equivalents DCP
and 3 equivalents HOAc in the mixed solvent of DCE and PhCl
(1:1) at 140 °C under 50 bar CO, which provided the desired
product 1aa in 71% isolated yield (Table 1, entry 22).
aReaction scale: 1a (0.2 mmol, 1 equiv), solvent (1 mL). bGC
yields were determined by using hexadecane as the internal
c
d
e
standard. 120 °C, CO (20 bar). 130 °C, CO (40 bar). 140 °C,
f
g
h
CO (40 bar). no CO. 140 °C, CO (50 bar). The isolated yield
was obtained from a reaction on a 0.4 mmol scale. DCE: 1,2-
Dichloroethane. DCP: dicumyl peroxide. DTBP: di-tert-butyl
peroxide. TBHP: tert-butyl hydroperoxide solution (70% in H2O).
TFA: trifluoroacetate. PTSA: p-toluenesulfonic acid. DMF = N,N-
dimethylformamide. PivOH: pivalic acid.
Table 1. Optimization of reaction conditions.a
Me source + additive
(equiv)
Entry
Solvent
Yieldb (%)
With the optimized reaction conditions in hand (Table 1,
entry 22), we next explored the substrate scope of the reaction
with a range of benzimidazoles. As shown in Scheme 2,
benzimidazoles with different kinds of alkyl groups, whether
short-chain alkyl groups or long-chain alkyl groups all could be
transferred into the corresponding products in 39-71% yields
(Scheme 2, 3aa-3af), and even a cyclopentyl group which
readily forms a cyclopentyl radical in the presence of an
oxidizing agent could also formed the desired products 1ad in
39% yields. Next, different aryl-containing alkyl functional group
1g-1i were investigated, all showed comparable reactivity and
gave the desired product 1ag-1ai in 51-60% yields. Moreover,
disubstituted functional groups on the benzimidazole also
reacted smoothly, offering the anticipated products in 65% and
51% yields, respectively (Scheme 2, 1aj, 1ak). However, it is
worth noting that 1-phenyl-1H-benzo[d]imidazole 1l could not be
converted under our optimized reaction conditions. In the case
of using 1-unsubstitued imidazole as the substrate, no desired
product could be detected.
1c
2c
3c
4c
5c
6c
7d
8d
DCE
DCP (1.5)
DCP (1.5)
DCP (1.5)
DCP (1.5)
DCP (1.5)
DCP (1.5)
DCP (1.5)
DCP (1.5) + TFA (1)
34
1,4-dioxane
DMF
trace
trace
7
PhCF3
PhCl
15
MeCN
DCE
10
42
DCE
54
DCE
DCP (1.5) + HOAc
(1)
9d
53
36
32
58
66
61
DCP (1.5) + PivOH
(1)
10d
11d
12e
13e
14e
DCE
DCE
DCE
DCE
DCE
Scheme 2. Acetylation of benzimidazoles.a
DCP (1.5) + PTSA
(1)
DCP (1.5) + HOAc
(1)
DCP (1.5) + HOAc
(3)
DCP (1.5) + HOAc
(6)
15e
16e
DCE
DCE
DCP (1) + HOAc (3)
DCP (2) + HOAc (3)
37
57
DTBP (1.5) + HOAc
(3)
17e
18e
19e
DCE
32
0
TBHP (1.5) + HOAc
(3)
DCE
aReaction conditions: 1a (0.4 mmol, 1.0 equiv), DCP (0.6 mmol,
1.5equiv), and HOAc (66 uL, 3.0 equiv) in DCE + PhCl (1:1, 2
mL) at 140 °C for 20 h under CO (50 bar), isolated yield.
DCP (1.5) + HOAc
(3)
DCE + PhCl (1:1)
DCE + PhCl (1:1)
70
DCP (1.5) + HOAc
(3)
20e,f
21e
22g
0
After exploring the scope of benzimidazoles, we turned to
examine the carbonylative acetylation of other heterocycles
under the standard conditions. Satisfactorily, isoquinoline 2a
could react with DCP to give the desired 1-(isoquinolin-1-
yl)ethan-1-one 2aa in 66% (Table 2, entry 1). Furthermore,
isoquinolines with diverse functional groups at the C4-position all
DCE + PhCl (1:1) HOAc (3)
0
DCP (1.5) + HOAc
(3)
DCE + PhCl (1:1)
75 (71)h
2
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10.1002/ejoc.201901728
European Journal of Organic Chemistry
COMMUNICATION
engaged in this reaction smoothly to form the corresponding
gave the target product 3aa in 69% isolated yield (Table 4, entry
1). Bromo substituted product 3ab can be prepared from the
corresponding 6-bromobenzo[d]thiazole 3b in 61% isolated yield
as well (Table 4, entry 2). Notably, monomethyl substituted,
monobromo substituted and dimethyl substituted thiazole were
progressed well and formed the corresponding desired low
boiling 1-(thiazol-2-yl)ethan-1-one products in moderate yields
(Table 4, entries 3-5).
products 2ab-2ad in moderate yields (57-58%).10
Table 2. Acetylation of isoquinolines.a
Yieldb
(%)
Entry
1
Isoquinoline
Product
Table 3. Optimization of reaction conditions for benzothiazole.a
66
Yieldb
(%)
Entry
Variations from the standard conditions
no catalyst, DCP, DCE+PhCl instead of
DTBP, PhCF3
1
2
3
13
2
3
57
58
-
73
(69)c
Cu(OAc)2, Fe(acac)3 or Co(OAc)2 instead of
Mn(acac)2
trace
4
Mn(OAc)3·2H2O instead of Mn(acac)2
MnF2 instead of Mn(acac)2
MeCN instead of PhCF3
EtOAc instead of PhCF3
DMF instead of PhCF3
added 5 mol% Bypridine
DCP instead of DTBP
no HOAc
70
68
66
51
21
56
68
33
0
5
6
7
4
57
8
9
aReaction conditions: 1a (0.4 mmol, 1.0 equiv.), DCP (0.6 mmol,
1.5equiv.), and HOAc (66 uL, 3.0 equiv.) in DCE + PhCl (1:1, 2
mL) at 140 °C for 20 h under CO (50 bar), isolated yield.
10
11
12
no CO
Subsequently, benzo[d]thiazole 3a was reacted with DCP
under the standard conditions. However, the desired product
3aa was detected only in 13% yield (Table 3, entry 1). After
systematic and extensive studies, to our delight, 69% of the
desired 1-(benzo[d]thiazol-2-yl)ethan-1-one 3aa can be isolated
formed, when the reaction was performed with 2.5 mol% of
Mn(acac)2 as catalyst, adding DTBP (1.5 equiv.) and HOAc (3
equiv.) in PhCF3 under pressure of CO (50 bar) at 140 °C (Table
3, entry 2). Only traces of the desired product could be detected
in the absence of Cu(OAc)2, Fe(acac)3 or Co(OAc)2 as the
catalyst (Table 3, entry 3). The yield of the reaction decreased to
70% and 68% respectively, when using Mn(OAc)3·2H2O or MnF2
instead of Mn(acac)2 as the catalyst (Table 3, entries 4-5). In
solvents screening, 21-66% yields of the desired product were
obtained in MeCN, EtOAc, or DMF (Table 3, entries 6-8). Then
2,2'-bipyridine as a ligand was tested, the yield of the desired
product cannot be further improved (Table 3, entry 9).
Additionally, no better yields could be obtained with DCP instead
of DTBP, or no HOAc (Table 1, entries 10-11). In the absence of
CO gas, no reaction occurred (Table 3, entry 12).
aReaction scale: 1a (0.2 mmol, 1 equiv.), solvent (1 mL). bGC
yields were determined by using hexadecane as the internal
c
standard. The isolated yield was obtained from a reaction on a
0.4 mmol scale.
Table 4. Acetylation of thiazoles.a
Entry
1
Oxime ester
Product
Yieldb (%)
69
2
3
61
56
Having determined the best conditions, the scope of
thiazoles was then examined under the optimized reaction
conditions. As shown in Table 4, unsubstituted benzothiazole 3a
3
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10.1002/ejoc.201901728
European Journal of Organic Chemistry
COMMUNICATION
55, 7227-7230; e) Y. Li, F. Zhu, Z. Wang, X.-F. Wu, ACS Catal., 2016,
6, 5561-5564.
4
5
41
42
[10] X.-F. Wu, Chem. Eur. J. 2015, 21, 12252-12265.
aReaction conditions: 1a (0.4 mmol, 1.0 equiv), Mn(acac)2 (0.01
mmol), DTBP (0.6 mmol, 1.5 equiv), and HOAc (66 uL, 3.0
equiv) in PhCF3 (2 mL) at 140 °C for 20 h under CO (50 bar),
isolated yield.
In conclusion, we have developed a new carbonylative
protocol for the acetylation of heterocycles. With peroxide as the
methyl source, the desired methyl heterocyclic ketone products
were obtained in moderate to good yields with complete
chemoselectivity.
Acknowledgements
The authors thank the Chinese Scholarship Council for financial
support. The analytical supports from Dr. W. Baumann, Dr. C.
Fischer, S. Buchholz, and S. Schareina (all in LIKAT) are
gratefully acknowledged.
Keywords: Carbonylation • Radical • Acetylation • Ketones •
Coupling
[1]
[2]
[3]
a) M. Chrzanowska, M. D. Rozwadowska, Chem. Rev. 2004, 104,
3341-3370; b) K. W. Bentley, Nat. Prod. Rep. 2005, 22, 249-268.
D. L. Klayman, J. P. Scovill, J. Bruce, J. F. Bartosevich, J. Med. Chem.,
1984, 27, 84-87.
a) X. Y. Zhu, J. R. Etukala, S. V. Eyunni, V. Setola, B. L. Roth, S. Y.
Ablordeppey, Eur. J. Med. Chem., 2012, 53, 124-132; b) S. Tsutsumi, T.
Okonogi, S. Shibahara, S. Ohuchi, E. Hatsushiba, A. A. Patchett, B. G.
Christensen, J. Med. Chem., 1994, 37, 3492-3502.
[4]
[5]
D. Valdez-Padilla, S. Rodríguez-Morales, A. Hernández-Campos, F.
Hernández-Luis, L. Yépez-Mulia, A. Tapia-Contreras, R. Castillo,
Bioorgan. Med. Chem., 2009, 17, 1724-1730.
a) X.-Z. Wang, C.-C. Zeng, Tetrahedron 2019, 75, 1425-1430; b) J. D.
Galloway, D. N. Mai, R. D. Baxter, Org. Lett., 2017, 19, 5772-5775; c)
X.-L. Chen, X. Li, L.-B. Qu, Y.-C. Tang, W.-P. Mai, D.-H. Wei, W.-Z. Bi,
L.-K. Duan, K. Sun, J.-Y. Chen, D. D. Ke, Y. F. Zhao, J. Org. Chem.,
2014, 79, 8407-8416; d) K. Matcha, A. P. Antonchick, Angew. Chem.,
Int. Ed., 2013, 52, 2082-2086.
[6]
For selected reviews on carbonylation published since 2019, see: a) J.-
B. Peng, F.-P. Wu, X.-F. Wu, Chem. Rev. 2019, 119, 2090-2127; b) J.-
B. Peng, H.-Q. Geng, X.-F. Wu, Chem 2019, 5, 526-552; c) K. Ma, B. S.
Martin, X. Yin, M. Dai, Nat. Prod. Rep. 2019, 36, 174-219; d) R.
Mancuso, N. Della Ca’, L. Veltri, I. Ziccarelli, B. Gabriele, Catalysts
2019, 9, 610-642; e) S. Zhao, N. P. Mankad, Catal. Sci. Technol. 2019,
9, 3603-3613.
[7]
a) H. Matsubara, T. Kawamoto, T. Fukuyama, I. Ryu, Acc. Chem. Res.,
2018, 51, 2023-2035; b) I. Ryu, N. Sonoda, Angew. Chem. Int. Ed.
Engl., 1996, 35, 1050-1066.
[8]
[9]
D. U. Nielsen, K. T. Neumann, A. T. Lindhardt, T. Skrydstrup, J. Label.
Compd. Radiopharm., 2018, 61, 949-987.
a) Y. Li, C. Wang, F. Zhu, Z. Wang, J. F. Soulé, P. H. Dixneuf, X.-F. Wu,
Chem. Commun., 2017, 53, 142-144; b) Z. Yin, Z. Zhang, J.-F. Soulé, P.
H. Dixneuf, X.-F. Wu, J. Catal., 2019, 372, 272-276; c) Z. Yin, J.
Rabeah, A. Brꢀckner, X.-F. Wu, Org. Lett., 2019, 21, 1766-1769; d) Y.
Li, K. Dong, F. Zhu, Z. Wang, X. F. Wu, Angew. Chem., Int. Ed., 2016,
4
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COMMUNICATION
Entry for the Table of Contents
Carbonylation
Herein, a new procedure for the carbonylative acetylation of heterocycles has been developed. In this process, organic peroxide acts
as the methyl source, various heterocycles were transformed into the corresponding methyl heterocyclic ketones in moderate to good
yields.
5
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