Synthesis of Pyrrole-2-carbaldehyde Derivatives by Oxidative Annulation and Direct Csp3-H to C - O Oxidation

Article abstract of DOI:10.1021/acs.orglett.7b03821

An efficient and practical de novo synthesis of pyrrole-2-carbaldehyde skeletons featuring oxidative annulation and C_sp3-H to C - O oxidation is presented, exemplified by the preparation of pyrrole-2-carbaldehyde derivatives from aryl methyl ketones, arylamines, and acetoacetate esters. Preliminary mechanistic investigations indicate that the aldehyde oxygen atom originates from oxygen. Moreover, the developed scalable approach provides a distinct advantage over traditional oxidative functionalization of C-H moieties, avoiding the use of stoichiometric quantities of hazardous oxidants.

Full text of DOI:10.1021/acs.orglett.7b03821

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Synthesis of Pyrrole-2-carbaldehyde Derivatives by Oxidative
Annulation and Direct C 3−H to CO Oxidation
sp
†
†
†
†
†
,†,‡
Xia Wu, Peng Zhao, Xiao Geng, Can Wang, Yan-dong Wu, and An-xin Wu*
†Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University,
Wuhan 430079, P. R. China
‡
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. China
*
S Supporting Information
ABSTRACT: An efficient and practical de novo synthesis of pyrrole-2-carbaldehyde skeletons featuring oxidative annulation and
C 3−H to CO oxidation is presented, exemplified by the preparation of pyrrole-2-carbaldehyde derivatives from aryl methyl
sp
ketones, arylamines, and acetoacetate esters. Preliminary mechanistic investigations indicate that the aldehyde oxygen atom
originates from oxygen. Moreover, the developed scalable approach provides a distinct advantage over traditional oxidative
functionalization of C−H moieties, avoiding the use of stoichiometric quantities of hazardous oxidants.
he aldehyde group is involved in numerous name1
reactions (e.g., Ugi, Prins, aldol, and Schmidt reactions),
with (hetero)aromatic aldehydes being versatile intermediates
Scheme 1. Oxidation of C−H Bond Functionalization To
Synthesize Ketones and Aldehydes
T
in the synthesis of pharmaceuticals, fragrances, fine chemicals,
2
and natural products. Due to the ubiquitous application of
(
hetero)aryl aldehydes, numerous classical (e.g., Vilsmeier−
Haack, Gattermann and Gattermann−Koch, Reimer−Tiemann,
and Duff reactions as well as the Rosenmund reduction) and
3
nonclassical (e.g.,C−C bond cleavage and photocatalytic
4
formylation) approaches are available for their synthesis.
However, the social and environmental demands for greener,
more atom-economical, and sustainable methods require the
development of alternative protocols such as direct oxidation of
C−H bonds to CO bonds, which represents an ideal
chemical synthesis as it does not involve the use of hazardous
oxidants/harsh reaction conditions and has unsurprisingly
5
attracted the increased attention of the scientific community.
Meanwhile, significant efforts have been directed toward the
development of more efficient catalytic processes in this field,
with considerable progress achieved during the past five years,
as exemplified by a gracefully scalable electrochemical oxidation
of nonactivated aliphatic methylene C−H bonds to ketone
fact that such reactions are beautifully developed, they feature
single oxidation of C−H to the CO bond. Direct de novo
synthesis of heteroaromatic aldehydes relying on C−H bond
oxidation has not yet been reported, mainly due to the difficulty
of achieving high selectivity and preventing overoxidation to
(hetero)benzoic acids. Therefore, developing oxidation
conditions for selective heteroaromatic aldehyde formation by
fine-turning the reaction parameters, especially those of de
novo synthesis, is an important synthetic task. Herein, we
report a de novo synthesis of pyrrole-2-carbaldehyde derivatives
from aryl methyl ketones, arylamines, and acetoacetate esters
6
groups described by Baran and co-workers. In parallel, photo-
1
0
or metal-catalyzed aerobic oxidation of (hetero)benzylic C−H
bonds to ketone CO bonds has been described by Lei, Xiao,
7
Shi, and others (Scheme 1a). More importantly, efficient and
highly selective catalytic oxidation of methyl C−H bonds to8
aldehyde CO groups has also been developed (Scheme 1b).
Moreover, metal-catalyzed intramolecular dehydrogenative
aminooxygenation or bioxygenation of alkenes and alkynes to
synthsize heterocyclic aldehydes have been described by
Received: December 6, 2017
9
Chemler, Shi, Zhu, and Zhang (Scheme 1c). Despite the
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03821
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
using selective C−H to CO oxidation as a key step (Scheme
Scheme 2. Scope of Aryl Methyl Ketones
1d).
Considering previously reported methods and the appeal of a
de novo synthesis, we investigated new reaction paradigms,
aiming to develop more efficient selective oxidation to
synthesize N-heteroaryl aldehydes. For this purpose, the
oxidative condensation of acetophenone 1a, 4-methoxyaniline
2
a, and ethyl acetoacetate 3a was selected as a model reaction,
affording ethyl 2-formyl-1-(4-methoxyphenyl)-5-phenyl-1H-
pyrrole-3-carboxylate 4a (a pyrrole-2-carbaldehyde derivative)
in 32% yield in the presence of a copper salt and iodine (Table
1, entry 1). The structure of 4a was unambiguously confirmed
a
Table 1. Optimization of the Reaction Conditions
b
entry
CuCl (equiv)
temp (°C)
I2 (equiv)
yield (%)
2
c
1
0.2
0.2
0.1
0.5
1.0
0.5
0.5
0.5
0.5
0.5
0.5
100
100
100
100
100
90
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.0
2.0
1.6
1.6
32
50
28
62
53
58
55
54
61
67
74
such as Me, OMe, Cl, Br, F, Ph, and NO (Scheme 2, 4b−l)
2
2
3
4
5
6
7
8
being well tolerated. The results indicated that the electronic
and steric properties of the aromatic ketone had little impact on
the efficiency of this reaction. The gram-scale reaction could
proceed very smoothly. Moreover, methyl ketone containing
naphthalene moiety could also be employed to the pyrrole
aldehyde scaffold without any difficulties (Scheme 2, 4m).
Notably, methyl ketones with heteroaryl groups such as
thiophenyl could also be employed, affording the correspond-
ing products in good yields (Scheme 2, 4n, 52%).
110
100
100
100
100
9
d
1
0
e
1
1
Further, we investigated the scope of arylamines and
acetoacetate esters, with the results displayed in Scheme 3
a
Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), 3a (1.0 mmol),
CuCl , and I heated in DMSO (4 mL) within 12 h. Products were
b
2
2
c
d
obtained in isolated yields. CuCl was used instead of CuCl . Under
2
Scheme 3. Scope of Arylamine and Acetate Esters
e
air. O balloon was used. PMP = 4-OMe-Ph.
2
by X-ray crystallography (for details, see the Supporting
Information). Notably, pyrrole and its derivatives have found
numerous applications in areas such as organocatalysis and
11
natural product/biologically active substance synthesis. After
a number of trials, the use of 0.5 equiv CuCl was found to be
2
optimal (entries 2−5 of Table 1; for more details, see the
Supporting Information), with the best yield (62%) obtained
for a 1a/2a/3a molar ratio of 1:1:1 (see the SI). Subsequently,
we varied the amount of iodine and temperature, achieving the
best results at 1.6 equiv of I and 100 °C (Table 1, entries 6−
2
1
0). Finally, screening of a series of amines and Brønsted/Lewis
acids as additives under these conditions showed that none of
them had a positive impact on the reaction yield (see the SI).
Pleasantly, the desired product 4a was obtained in 67% yield
upon prolonged exposure of the reaction mixture to air (Table
1
, entry 10). Moreover, the reaction yield was further increased
when a O balloon was used (Table 1, entry 11). After several
2
experimental optimizations, the optimized conditions were
determined as 1a (1.0 mmol), 2a (1.0 mmol), and 3a (1.0
mmol) in the presence of I (1.6 mmol), CuCl (0.5 mmol),
2
2
and O in DMSO at 100 °C to afford the desired product in
indicating that anilines with electron-donating, electron-with-
drawing, and halogen groups such as Me, OMe, I, Br, F, Ph,
2
7
4% yield (Table 1, entry 11).
With the optimized conditions in hand, we tested the
NO , and COOEt could be successfully utilized, furnishing the
2
substrate scope of this iodine/copper-mediated selective
oxidation (Scheme 2), showing that the reaction could be
readily extended to a variety of aryl-substituted methyl ketones
desired products in moderate to good yields (Scheme 3, 5a−h).
Importantly, halo-substituted products could be used for
further transformations. Furthermore, the phenyl ring could
be replaced by a naphthalene moiety (Scheme 3, 5j). In
1
, with both electron-withdrawing and -donating substituents
B
DOI: 10.1021/acs.orglett.7b03821
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
addition, a number of acetoacetate esters 3 were suitable for
this reaction, smoothly reacting with 1d and 2a to afford the
desired products in moderate to good yields (Scheme 3, 5k−
m).
Scheme 5. Labeling Experiments
To gain insight into the reaction mechanism, the following
experiments were performed. Acetophenone (1a, 1.0 mmol)
was heated under standard conditions to give phenylglyoxal 1ab
and the corresponding hydrated species 1ac in quantitative
yield (Scheme 4a). Moreover, α-iodoketone 1aa and hydrated
1
3
using acetophenone-β,β,β-d3 and acetophenone-β- C as
substrates, respectively, with the corresponding products 4a-
Scheme 4. Control Experiments
d and 4a′ obtained in 71 and 70% yields. The obtained results
1
indicated that methyl ketones provide two carbons for the
construction of the pyrrole ring.
Based on the above findings and previously reported
12
results, we propose a plausible reaction mechanism for the
representative reaction of 1a, 2a, and 3a (Scheme 6). In this
Scheme 6. Proposed Mechanism
mechanism, 1a is converted to phenylglyoxal 1ab, releasing HI
and dimethyl sulfide (DMS) via sequential iodination/
Kornblum oxidation. Concomitantly, the condensation of 3a
with 2a affords intermediate A, which undergoes tautomeriza-
tion to give 3aa. Subsequently, 1ab is activated by Lewis acidic
I2 or copper salt and reacts with 3aa via in situ cross-trapping to
yield intermediate B, which undergoes dehydration/cycliza-
tion/oxidative aromatization to produce intermediate 4aa. In
species 1ac were reacted with 2a and 3a under standard
conditions (Schemes 4b,c), giving the desired product 4a in
8
1
0% and 67% yields, respectively, and confirming that 1aa and
ac were key intermediates. Subsequently, preformed enami-
none 3aa was reacted with 1ac under different conditions
Scheme 4d), and the results indicated that 3aa is a key
(
intermediate and implied that the oxygen atom of aldehyde
group does not originate from DMSO. The experiments also
II
the next step, 4aa is directly oxidized by Cu to afford radical D
I
+
highlighted the crucial role of CuCl which is more efficient in
and generate Cu and H . Intermediate D easily reacts with
molecular oxygen to form E, a peroxy radical, which is reduced
2
promoting the reaction than iodine. Next, the product 4a was
obtained in trace when using argon protection. Moreover, 3aa
was reacted with 1ac under argon for 2 h, affording 4a in 72%
yield after subsequent exposure of the reaction to oxygen
I
by Cu and protonated to generate intermediate F. Finally, F
eliminates H O to produce the desired 4a. Alternatively, a small
2
amount of intermediate 4aa maybe undergo a rapid oxidation
reaction with iodine and oxygen to form product 4a.
In summary, we have developed an unprecedented de novo
synthesis of pyrrole-2-carbaldehyde derivatives based on I2/
(
Scheme 4e,f). Meanwhile, the reaction of 3aa and 1ac was
1
8
investigated in the presence of H O (10 equiv); however, no
2
1
8
18
O-labeled product ( O-4a) was detected (Scheme 4g). The
above results indicated that oxygen atom of aldehyde group of
a was derived from oxygen. Finally, enaminone 3aa was
CuCl -mediated oxidative cross-coupling/annulation/C−H
2
4
oxidation, exemplified by the formation of 2-formylpyrrole
derivatives under mild conditions. The above transformation
tolerates a wide range of aryl methyl ketones, arylamines, and
acetoacetate esters, affording polysubstituted pyrroles bearing
an aldehyde group. Further research on this synthetic strategy
and its applications is currently underway in our laboratory and
will be reported in due course.
reacted under standard conditions and no product 3aa′ was
yielded. The results further implied that the aldehyde group was
formed from the intermediate 4aa.
To develop a better understanding of the reaction
mechanism, we performed D-labeling (Scheme 5a) and 13C-
labeling (Scheme 5b) experiments under optimized conditions,
C
DOI: 10.1021/acs.orglett.7b03821
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
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S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03821.
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Experimental procedures, product characterizations,
1
13
crystallographic data, and H and C NMR spectra
PDF)
(
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AUTHOR INFORMATION
■
*
Corresponding Author
E-mail: chwuax@mail.ccnu.edu.cn.
1
4046. (h) Sterckx, H.; De Houwer, J.; Mensch, C.; Caretti, I.;
Tehrani, K. A.; Herrebout, W. A.; Doorslaerb, S. V.; Maes, B. U. W.
Chem. Sci. 2016, 7, 346. (i) Miao, C. X.; Zhao, H. Q.; Zhao, Q. Y.; Xia,
C. G.; Sun, W. Catal. Sci. Technol. 2016, 6, 1378. (j) Shen, D.; Miao, C.
X.; Wang, S. F.; Xia, C. G.; Sun, W. Org. Lett. 2014, 16, 1108.
ORCID
An-xin Wu: 0000-0001-7673-210X
Notes
(
k) Hruszkewycz, D. P.; Miles, K. C.; Thiel, O. R.; Stahl, S. S. Chem.
Sci. 2017, 8, 1282.
8) (a) Gaster, E.; Kozuch, S.; Pappo, D. Angew. Chem., Int. Ed. 2017,
6, 5912. (b) Wang, Y.; Bauer, J. O.; Strohmann, C.; Kumar, K. Angew.
The authors declare no competing financial interest.
(
5
ACKNOWLEDGMENTS
Chem., Int. Ed. 2014, 53, 7514. (c) Sarma, B. B.; Efremenko, I.;
Neumann, R. J. Am. Chem. Soc. 2015, 137, 5916. (d) Lumb, J. P.
Angew. Chem., Int. Ed. 2017, 56, 9276.
■
This work was supported by the National Natural Science
Foundation of China (Grant Nos. 21472056 and 21602070).
We also thank Dr. Chuanqi Zhou, Hebei University, for
analytical support. This work was supported by “The
Fundamental Research Funds for the Central Universities”
(9) (a) Peng, H. H.; Akhmedov, N. G.; Liang, Y. F.; Jiao, N.; Shi, X.
D. J. Am. Chem. Soc. 2015, 137, 8912. (b) Wdowik, T.; Chemler, S. R.
J. Am. Chem. Soc. 2017, 139, 9515. (c) Wang, H. G.; Wang, Y.; Liang,
D. D.; Liu, L. Y.; Zhang, J. C.; Zhu, Q. Angew. Chem., Int. Ed. 2011, 50,
5678.
(
CCNU15ZX002). This work was also supported by the 111
Project B17019.
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Res. Dev. 1998, 2, 255. (b) Ishii, Y.; Iwahama, T.; Sakaguchi, S.;
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