Pd-Catalyzed Triple-Fold C(sp2)-H Activation with Enaminones and Alkenes for Pyrrole Synthesis via Hydrogen Evolution

Article abstract of DOI:10.1021/acs.orglett.1c01301

The synthesis of NH-free pyrroles via Pd-catalyzed annulation of enaminones and alkenes is reported. With the catalysis of Pd(II), the activation of triple C(sp2)-H bonds, including one internal C(sp2)-H bond in enaminone, has been activated to provide various pyrroles. The interesting evolution of hydrogen gas from the reactions has been observed by a hydrogen detector.

Full text of DOI:10.1021/acs.orglett.1c01301

pubs.acs.org/OrgLett
Letter
Pd-Catalyzed Triple-Fold C(sp2)−H Activation with Enaminones and
Alkenes for Pyrrole Synthesis via Hydrogen Evolution
Leiqing Fu, Yunyun Liu,* and Jie-Ping Wan*
Cite This: Org. Lett. 2021, 23, 4363−4367
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: The synthesis of NH-free pyrroles via Pd-catalyzed
annulation of enaminones and alkenes is reported. With the catalysis
of Pd(II), the activation of triple C(sp2)−H bonds, including one
internal C(sp2)−H bond in enaminone, has been activated to
provide various pyrroles. The interesting evolution of hydrogen gas
from the reactions has been observed by a hydrogen detector.
bonds13 for the synthesis of diversely functionalized pyrroles.
Interestingly, although a plethora of different alkenes have
been successfully used as reaction partners of stable enamines
for pyrrole synthesis, no known method has hitherto been
found to tolerate the transformation of acrylates for the
synthesis of corresponding pyrrole products. Considering the
important and broad application of acrylates in the C−H
alkenylation reactions,14 it is thus highly demanding to
establish new methods by activating the C−H bond of
acrylates and enamines for the synthesis pyrroles with
expanded product diversity.
Recently, the dehydrogenative transformations on C−H
and/or heteroatom-H bonds via hydrogen evolution has
emerged as a drastically sustainable tool in constructing new
C−C or C−heteroatom bonds.15 Actually, the dehydrogen-
ation of alcohols and amino alcohols has already been realized
with significant success in the synthesis of pyrroles by releasing
the hydrogen gas via alcohol transformation.16 However,
hydrogen evolution via the activation of the stable C−H bond
has not yet been reported for the construction of a pyrrole ring.
In combination with the recent progress in the vinyl C−H
activation and functionalization disclosed by us and others17 as
well as the recent emphasis in developing novel synthetic
methods via aryl ring construction using polar alkenes,18 we
report herein a new method on the synthesis of pyrroles via
s one of the fundamental heteroaryl motifs showing
1
Aprevalent applications in multidisciplinary areas,
the
pyrrole ring has been an attractive target throughout the
development of synthetic chemistry. The classical Paal−Knorr
reaction,2 Knorr reaction,3 and Hantzsch reaction,4 for
example, have contributed enormously to the advances of
pyrrole chemistry. However, following the daily increasing
demand in molecular diversity-, sustainability-, and safety-
oriented synthetic strategies, devising alterative and/or
complementary methods for pyrrole synthesis has emerged
as a significant goal in the science of synthesis.5 As one novel
example of a newly emerged tool in pyrrole synthesis, the
cascade annulation involving the key activation of one or more
C−H bonds has brought an important breakthrough. For
example, Stuart and co-workers reported the Rh(III)/Cu(II)-
catalyzed annulation of enamides and alkynes for pyrrole
synthesis via a key addition of the enamide C−H bond to the
alkyne.6 Glorius et al. developed the pyrrole ring construction
via Pd(II)-catalyzed intramolecular C−H alkenylation of
imines.7 Ellmann and co-workers disclosed the reactions of
enone-derived oxime esters and imines for pyrrole synthesis via
Rh-catalyzed alkenyl C−H functionalization.8 In addition,
reactions featured with C−H bond conversion in various other
substrates have also been developed as practical protocols
toward diverse pyrrole scaffolds.9
Among the designated methods for pyrrole synthesis via C−
H activation or functionalization, however, enamines have
been identified as most frequently used and reliable substrates.
With the catalysis of proper transition metal reagents, stable
enamines such as enaminones, enaminoesters, enaminonitriles,
etc. have been used to couple alkynes,10 alkenes,11 diazoesters/
hydrazones,12 or functionalization of intramolecular C−H
Received: April 16, 2021
Published: May 20, 2021
https://doi.org/10.1021/acs.orglett.1c01301
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4363−4367
4363

Organic Letters
pubs.acs.org/OrgLett
Letter
a,b
hydrogen evolution-based coupling of three stable C−H bonds
and an N−H bond by the reactions of simple enaminones and
acrylates. In addition, the synthesis of conjugate dienamines
has also been realized via catalytic addition of enaminones to
propiolates. The efficient transformation of these dienamines
into the titled pyrroles has provided strong evidence in
elucidating the possible reaction mechanism.
Scheme 1. Substrate Scope on Pyrrole Synthesis
Initially, the reaction of enaminone 1a and methyl acrylate
2a was conducted under different conditions for the synthesis
of pyrrole product 3a. Systematical screening on the catalyst,
additive, medium, temperature, reagents loading, etc. was
executed (see full data in the Supporting Information). As
outlined by the typical data (Table 1), the simultaneous
a
Table 1. Typical Results on the Condition Optimization
b
entry
variation from the general conditions
no variation
Pd(OAc)2 (0.01 mmol) and CuBr2 (0.1 mmol)
Pd(OAc)2 (0.01 mmol), no CuBr2
CuBr2 (0.1 mmol) and no Pd(OAc)2
reaction at 40 °C
reaction at 60 °C
with 0.7 mmol 2a, at 60 °C
with 0.7 mmol 2a, 60 °C
with 0.7 mmol 2a, 60 °C and 0.5 mL of DMF
yield (%)
1
2
3
4
5
6
7
43
24
0
0
44
48
55
63
71
a
Reaction conditions: 1 (0.2 mmol), 2 (0.7 mmol), DMF (0.5 mL),
b
reacted under air for 12 h. The H2 was detected by H2 detector.
c
Yield from 1 mmol scale reaction.
c
8
c
9
a
pyrroles bearing fused aryl (3ag and 3ah, Scheme 1) and
heteroaryl groups (3ag and 3ah, Scheme 1) were also
smoothly acquired by employing corresponding fused and
heteroaryl-functionalized enaminones. Nevertheless, no ex-
pected products were observed when N-substituted enami-
nones, dimedone-derived cyclic NH2-enaminone, and pentane-
2,4-dione-derived alkyl NH2-enaminone was independently
used to react with acrylate 2a under the standard conditions
(Scheme S2 in the Supporting Information). Additionally, the
reaction of aniline with 2a was conducted with the standard
catalytic conditions. However, no evident reaction was
observed.
Interestingly, by means of modifying the reaction conditions,
we were pleased to find that CuI could catalyze the C−H bond
addition of enaminones to alkyl propiolates 4 for the selective
synthesis of conjugate dienamines 5 with good to excellent
yields. As depicted in Scheme 2, different alkyl acrylates (5a−
5c, Scheme 2), as well as enaminones possessing functional
groups such as halogen, methyl, methoxy, etc. in either the
meta or para position (5d−5g, Scheme 2) provided
corresponding products with satisfactory yields. Notably, this
C−H addition also tolerated well the furan-functionalized
enaminone and enaminoester (5h and 5i, Scheme 2).
Corresponding dienamines with different β-substitutions (R2
= n-Pr or Ph) were also practically furnished (5j or 5k, Scheme
2).
General conditions: 1a (0.2 mmol), 2a (0.4 mmol), Pd(OAc)2 (0.02
mmol), CuBr2 (0.2 mmol) in DMF (2 mL). Stirred at 80 °C for 12 h.
b
c
Isolated yield. With additional AgOAc (0.03 mmol).
employment of Pd(II) and Cu(II) reagent was mandatory
(entries 1−4, Table 1). In addition, conducting the reaction at
a mild temperature of 60 °C was favorable to give better results
(entries 5−6, Table 1). On the other hand, increasing the
loading of 2a also proved to be practical in improving the
product yield (entry 7, Table 1). Notably, reducing the volume
of reaction medium and employing additionally AgOAc as
additive was able to further enhance the yield of 3a,
respectively (entries 7−9, Table 1).
Under the optimal conditions, the scope and limitations of
this method in synthesizing pyrroles 3 were investigated.19 On
one hand, when enaminone 1a was fixed to react with different
acrylic ester substrates, the products containing a methyl, ethyl,
n-butyl, tert-butyl, or benzyl group (3a−3e and 3q−3u,
Scheme 1) were afforded in good yields. The extension of
the alkene component to internal alkenyl ester, enone, vinyl
nitrile, vinyl amide, styrene, and α-allylnaphthalene was also
conducted, but none gave the expected pyrrole product under
the present conditions (see also Scheme S2 in the Supporting
Information). For the enaminones 1, on the other hand,
electron-withdrawing groups such as F, Cl, Br, I, and CN (3f−
3n and 3v−3y, Scheme 1) and electron-donating groups such
as alkyl- and alkoxyl-substituted phenyl enaminones (3o−3u,
3z−3ac, Scheme 1) showed general tolerance to the synthesis.
Slightly lower yields were observed in the reactions employing
enaminones functionalized with electron-withdrawing groups.
Moreover, enaminones featuring more than one substituent in
the phenyl ring also took part in the synthesis to afford good
results (3al−3ao, Scheme 1). As expected, the synthesis of
Having been inspired by the tunable synthesis of dienamines
5, we thought that such compounds were the possible
intermediate during the formation of the pyrrole products.
Accordingly, these dienamines were found to undergo
intramolecular dehydrogenative C−H amination to provide
pyrroles 3 with high efficiency under the standard Pd-catalytic
conditions. Besides providing products that had been
4364
https://doi.org/10.1021/acs.orglett.1c01301
Org. Lett. 2021, 23, 4363−4367

Organic Letters
pubs.acs.org/OrgLett
Letter
a
Scheme 2. Synthesis of Conjugate Dienamines
Scheme 4. Plausible Reaction Mechanism
a
Reaction conditions: 1 (0.2 mmol), 4 (0.4 mmol), MeCN (2.0 mL),
stirred under air for 24 h; isolated yield was reported.
synthesized via the direct enamine−acrylate annulation (3a,b,
3d, 3h, 3q, 3x, and 3z, Scheme 3), the intramolecular version
Scheme 3. Synthesis of Pyrroles from Various
a,b
Dienamines
which has been observed with HMRS from the reaction
residue (see the Supporting Information). The dehydrogen-
ative C-,N-palladation of 5b with Pd(II) gives rise to
palladacycle C, which undergoes reductive elimination to
yield the pyrrole product. The Pd(0) released thereby can be
regenerated in the presence of a Cu(II) terminal oxidant.
In conclusion, we have developed a method for the synthesis
of NH-free pyrroles with the dehydrogenative coupling of
enaminones and alkenes via Pd-catalyzed activation of triple
C(sp2)−H bonds. The reaction represents a good tolerance of
a broad scope of enaminones and acrylates. In addition, we
also obtained a variety of conjugate dienamines by utilizing
various enaminones and propiolates, and the dienamines could
be transformed to NH-free pyrroles under optimal conditions.
Mechanistic studies suggested that dienamine was most likely
to be an active intermediate during the whole reaction.
a
Reaction conditions: 5 (0.2 mmol) in DMF (0.5 mL), stirred for 12
b
h under air; isolated yield was reported. The H2 was detected by H2
detector.
was found to be capable of providing new pyrrole products that
could not be accessed by the above annulation protocol (3ap−
3as, Scheme 3). Moreover, hydrogen evolution was observed
from the reaction, further supporting that 5 were key reaction
intermediates also in the enamine−acrylate annulation.
However, directly employing enaminone 1a and methyl
propiolate (4a) to the standard conditions in Scheme 1 did
not provide pyrrole 3a.
For the sake of gaining more information on the reaction
process, some control experiments were also designed. First,
pyrrole 3b and dienamine 5b were obtained by performing the
reaction of 1a and 2a at room temperature (eq 1). In addition,
3b could not be obtained without employing the metal
reagents, confirming the indispensable role of metal in the
reaction (eq 2).
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01301.
Experimental procedures, hydrogen gas determination,
characterization data, and HRMS and NMR spectra
(PDF)
According to the clues provided by the control experiments,
a mechanism for this NH-free pyrrole synthesis has been
proposed. As outlined in Scheme 4, the reaction of AgOAc and
PdCl2 may provide active PdIIXL which couples enaminone to
deliver Pd(II) intermediate A via the C−H insertion.20 The
1,2-migratory insertion of the alkene to A leads to the
formation of palladacycle species B. The featured β-H
elimination from B provides dienamine intermediate 5b,
Accession Codes
CCDC 2076610 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
4365
https://doi.org/10.1021/acs.orglett.1c01301
Org. Lett. 2021, 23, 4363−4367

Organic Letters
pubs.acs.org/OrgLett
Letter
(5) (a) Estévez, V.; Villacampa, M.; Menéndez, J. C. Recent
advances in the synthesis of pyrroles by multicomponent reactions.
Chem. Soc. Rev. 2014, 43, 4633−4657. (b) Zhou, Y.; Zhou, L.;
Jesikiewicz, L. T.; Liu, P.; Buchwald, S. L. Synthesis of Pyrroles
through the CuH-Catalyzed Coupling of Enynes and Nitriles. J. Am.
Chem. Soc. 2020, 142, 9908−9914. (c) Xiao, P.; Yuan, H.; Liu, J.;
Zheng, Y.; Bi, X.; Zhang, J. Radical Mechanism of Isocyanide-Alkyne
Cycloaddition by Multicatalysis of Ag2CO3, Solvent, and Substrate.
ACS Catal. 2015, 5, 6177−6184. (d) Li, J.-K.; Zhou, B.; Tian, Y.-C.;
Jia, C.; Xue, X.-S.; Zhang, F.-G.; Ma, J.-A. Potassium Acetate-
Catalyzed Double Decarboxylative Transannulation To Access Highly
Functionalized Pyrroles. Org. Lett. 2020, 22, 9585−9590. (e) Cheng,
B.-Y.; Wang, Y.-N.; Li, T.-R.; Lu, L.-Q.; Xiao, W.-J. Synthesis of
Polysubstituted Pyrroles through a Formal [4 + 1] Cycloaddition/
E1cb Elimination/Aromatization Sequence of Sulfur Ylides and α,β-
Unsaturated Imines. J. Org. Chem. 2017, 82, 12134−12140.
(f) Gilbert, Z. W.; Hue, R. J.; Tonks, I. A. Catalytic formal [2 +
2+1] synthesis of pyrroles from alkynes and diazenes via TiII/TiIV
redox catalysis. Nat. Chem. 2016, 8, 63−68. (g) Liu, Y.; Parodi, A.;
Battaglioli, S.; Monari, M.; Protti, S.; Bandini, M. Visible-Light-Driven
Synthesis of 1,3,4-Trisubstituted Pyrroles from Aryl Azides. Org. Lett.
2019, 21, 7782−7786.
(6) Stuart, D. R.; Alsabeh, P.; Kuhn, M.; Fagnou, K. Rhodium(III)-
Catalyzed Arene and Alkene C-H Bond Functionalization Leading to
Indoles and Pyrroles. J. Am. Chem. Soc. 2010, 132, 18326−18339.
(7) Shi, Z.; Suri, M.; Glorius, F. Aerobic Synthesis of Pyrroles and
Dihydropyrroles from Imines: Palladium(II)-Catalyzed Intramolecu-
lar C-H Dehydrogenative Cyclization. Angew. Chem., Int. Ed. 2013, 52,
4892−4896.
(8) Lian, Y.; Huber, T.; Hesp, K. D.; Bergman, R. G.; Ellmann, J. A.
Rhodium(III)-Catalyzed Alkenyl C-H Bond Functionalization:
Convergent Synthesis of Furans and Pyrroles. Angew. Chem., Int. Ed.
2013, 52, 629−633.
(9) (a) Kumar, P.; Kapur, M. Catalyst Control in Positional-
Selective C-H Alkenylation of Isoxazoles and a Ruthenium-Mediated
Assembly of Trisubstituted Pyrroles. Org. Lett. 2019, 21, 2134−2138.
(b) Zheng, J.; Huang, L.; Huang, C.; Wu, W.; Jiang, H. Synthesis of
Polysubstituted Pyrroles via Pd-Catalyzed Oxidative Alkene C-H
Bond Arylation and Amination. J. Org. Chem. 2015, 80, 1235−1242.
(c) Yang, W.; Liu, X.; Leung, P.-H.; Li, Y.; Yang, D.; Chen, Y. Iron-
Mediated Ring-Opening and Rearrangement Cascade Synthesis of
Polysubstituted Pyrroles from 4-Alkenylisoxazoles. Adv. Synth. Catal.
2020, 362, 1868−1876.
(10) (a) Rakshit, S.; Patureau, F. W.; Glorius, F. Pyrrole Synthesis
via Allylic sp3 C-H Activation of Enamines Followed by
Intermolecular Coupling with Unactivated Alkynes. J. Am. Chem.
Soc. 2010, 132, 9585−9587. (b) Ke, J.; He, C.; Liu, H.; Li, M.; Lei, A.
Oxidative cross-coupling/cyclization to build polysubstituted pyrroles
from terminal alkynes and β-enamino esters. Chem. Commun. 2013,
49, 7549−7551. (c) Yan, R.-L.; Luo, J.; Wang, C.-X.; Ma, C.-W.;
Huang, G.; Liang, Y.-M. Cu (I)-Catalyzed Synthesis of Polysub-
stituted Pyrroles from Dialkyl Ethylenedicarboxylates and β-Enamino
Ketones or Esters in the Presence of O2. J. Org. Chem. 2010, 75,
5395−5397.
AUTHOR INFORMATION
■
Corresponding Authors
Yunyun Liu − College of Chemistry and Chemical Engineering,
Jiangxi Normal University, Nanchang 330022, P. R. China;
orcid.org/0000-0002-5553-1672;
Email: chemliuyunyun@jxnu.edu.cn
Jie-Ping Wan − College of Chemistry and Chemical
Engineering, Jiangxi Normal University, Nanchang 330022,
P. R. China; orcid.org/0000-0002-9367-8384;
Email: wanjieping@jxnu.educn
Author
Leiqing Fu − College of Chemistry and Chemical Engineering,
Jiangxi Normal University, Nanchang 330022, P. R. China;
College of Chemistry and Bio-Engineering, Yichun University,
Yichun, Jiangxi 336000, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01301
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The work is supported by National Natural Science
Foundation of China (21861019, 21562025) and the Natural
Science Foundation of Jiangxi Province (20202ACBL203006).
REFERENCES
■
(1) (a) Shimizu, S. Recent Advances in Subporphyrins and
Triphyrin Analogues:Contracted Porphyrins Comprising Three
Pyrrole Rings. Chem. Rev. 2017, 117, 2730−2784. (b) Ahmad, S.;
Alam, O.; Naim, M. J.; Shaquiquzzaman, M.; Alam, M.; Iqbal, M.
Pyrrole: An insight into recent pharmacological advances with
structure activity relationship. Eur. J. Med. Chem. 2018, 157, 527−
561. (c) Jiang, X.; Yue, S.; Chen, K.; Shao, Z.; Li, C.; Su, Y.; Zhao, J.
Synthesis, properties and application of novel 5,6,5,6-tetracyclic
pyrazine/pyrrole-fused unsymmetric bis(BF2) fluorescent dyes:
BOPYPYs. Chin. Chem. Lett. 2019, 30, 2271−2273. (d) Najari, A.;
Beaupre, S.; Berrouard, P.; Zou, Y.; Pouliot, J. R.; Lepage-Perusse, C.;
Leclerc, M. Synthesis and Characterization of New Thieno[3,4-
c]pyrrole-4,6-dione Derivatives for Photovoltaic Applications. Adv.
Funct. Mater. 2011, 21, 718−728.
(2) (a) Knorr, L. Ber. Synthese von Furfuranderivaten aus dem
̈
Diacetbernsteinsaureester. Ber. Dtsch. Chem. Ges. 1884, 17, 2863−
2870. (b) Paal, C. Ber. Ueber die Derivate des Acetophenonace-
tessigesters und des Acetonylacetessigesters. Ber. Dtsch. Chem. Ges.
1884, 17, 2756−2767. (c) Balakrishna, A.; Aguiar, A.; Sobral, P. J. M.;
Wani, M. Y.; Silva, J. A.; Sobra, A. J. F. N. Paal-Knorr synthesis of
pyrroles: from conventional to green synthesis. Catal. Rev.: Sci. Eng.
2019, 61, 84−110. (d) Kornienko, A.; La Clair, J. J. Covalent
modification of biological targets with natural products through Paal−
Knorr pyrrole formation. Nat. Prod. Rep. 2017, 34, 1051−1060.
(3) (a) Knorr, L. Synthetische Versuche mit dem Acetessigester. II.
(11) (a) Liu, P.; Liu, J.-l.; Wang, H.-s.; Pan, Y.-m.; Liang, H.; Chen,
Z.-F. Copper-mediated cross-coupling−cyclization-oxidation: a one-
pot reaction to construct polysubstituted pyrroles. Chem. Commun.
2014, 50, 4795−4698. (b) Senadi, G. C.; Hu, W.-P.; Garkhedkar, A.
M.; Boominathan, S. S. K.; Wang, J.-J. Palladium(II)-catalysed
regioselective synthesis of 3,4-disubstituted quinolines and 2,3,5-
trisubstituted pyrroles from alkenes via anti-Markovnikov selectivity.
Chem. Commun. 2015, 51, 13795−13798. (c) Chen, J.; Chang, D.;
Xiao, F.; Deng, G.-J. Three-Component Ordered Annulation of
Amines, Ketones, and Nitrovinylarenes: Access to Fused Pyrroles and
Substituted Indoles under Metal-Free Conditions. J. Org. Chem. 2019,
84, 568−578.
Mittheilung: Ueberfuhrung des Diacetbernsteinsaureesters und des
̈
̈
Acetessigesters in Pyrrolderivate. Justus Liebigs Ann. Chem. 1886, 236,
290. (b) Knorr, L.; Lange, H. Ber. Ueber die Bildung von
Pyrrolderivaten aus Isonitrosoketonen. Ber. Dtsch. Chem. Ges. 1902,
35, 2998−3008.
(4) (a) Hantzsch, A. Ber. Neue Bildungsweise von Pyrrolderivaten.
Ber. Dtsch. Chem. Ges. 1890, 23, 1474. (b) Estévez, V.; Villacampa,
M.; Menéndez, J. C. Three-component access to pyrroles promoted
by the CAN-silver nitrate system under high-speed vibration milling
conditions: a generalization of the Hantzsch pyrrole synthesis. Chem.
Commun. 2013, 49, 591−593.
(12) (a) Luo, K.; Mao, S.; He, K.; Yu, X.; Pan, J.; Lin, J.; Shao, Z.;
Jin, Y. Highly Regioselective Synthesis of Multisubstituted Pyrroles via
Ag-Catalyzed [4 + 1C]insert Cascade. ACS Catal. 2020, 10, 3733−
4366
https://doi.org/10.1021/acs.orglett.1c01301
Org. Lett. 2021, 23, 4363−4367

Organic Letters
pubs.acs.org/OrgLett
Letter
3740. (b) Li, M.; Sun, Y.; Xie, Y.; Yu, Y.; Huang, F.; Huang, H.
Copper-catalyzed carbene insertion and ester migration for the
synthesis of polysubstituted pyrroles. Chem. Commun. 2020, 56,
11050−11053.
Enaminone-Based Alkynyl Sulfides under Ambient Conditions. Org.
Lett. 2020, 22, 6557−6561. (d) Wang, F.; Sun, W.; Wang, Y.; Jiang,
Y.; Loh, T.-P. Highly Site-Selective Metal-Free C-H Acyloxylation of
Stable Enamines. Org. Lett. 2018, 20, 1256−1260. (e) Yuan, Y.; Hou,
W.; Zhang-Negrerie, D.; Zhao, K.; Du, Y. Direct Oxidative Coupling
of Enamines and Electron-Deficient Amines: TBAI/TBHP-Mediated
Synthesis of Substituted Diaminoalkenes under Metal-Free Con-
ditions. Org. Lett. 2014, 16, 5410−5413. (f) Mkrtchyan, S.;
Iaroshenko, V. O. Visible-light-mediated arylation of ortho-hydrox-
yarylenaminones: direct access to isoflavones. Chem. Commun. 2020,
56, 2606−2609. (g) Bagle, P. N.; Mane, M. V.; Sancheti, S. P.; Gade,
A. B.; Shaikh, S. R.; Baik, M.-H.; Patil, N. T. Gold(I)-Catalyzed
Hydroxy Group Assisted C(sp2)-H Alkylation of Enaminones with
Diazo Compounds to Access 3-Alkyl Chromones. Org. Lett. 2019, 21,
335−339.
(13) (a) Yugandar, S.; Konda, S.; Ila, H. Amine Directed Pd(II)-
Catalyzed C-H Activation-Intramolecular Amination of N-Het(aryl)/
Acyl Enaminonitriles and Enaminones: An Approach towards
Multisubstituted Indoles and Heterofused Pyrroles. J. Org. Chem.
2016, 81, 2035−2052. (b) Li, X.; Chen, M.; Xie, X.; Sun, N.; Li, S.;
Liu, Y. Synthesis of Multiple-Substituted Pyrroles via Gold(I)-
Catalyzed Hydroamination/Cyclization Cascade. Org. Lett. 2015,
17, 2984−2987. (c) Golantsov, N. E.; Golubenkova, A. S.; Festa, A.
A.; Varlamov, A. V.; Voskressensky, L. G. A Domino Route toward
Polysubstituted Pyrroles from 2-Imidazolines and Electron-Deficient
Alkynes. Org. Lett. 2020, 22, 4726−4731.
(18) (a) Gu, Z.-Y.; Zhu, T.-H.; Cao, J.-J.; Xu, X.-P.; Wang, S.-Y.; Ji,
S.-J. Palladium-Catalyzed Cascade Reactions of Isocyanides with
Enaminones: Synthesis of 4-Aminoquinoline Derivatives. ACS Catal.
2014, 4, 49−52. (b) Hu, D.; Yang, L.; Wan, J.-P. Biaryl and
atropisomeric biaryl aldehyde synthesis by one-step, metal-free
benzannulation of aryl enals and propiolates. Green Chem. 2020, 22,
6773−6777. (c) Yang, L.; Wan, J.-P. Ethyl lactate-involved three-
component dehydrogenative reactions: biomass feedstock in diversity-
oriented quinoline synthesis. Green Chem. 2020, 22, 3074−3078.
(d) Zhao, M.-N.; Ren, Z.-H.; Yang, D.-S.; Guan, Z.-H. Iron-Catalyzed
Radical Cycloaddition of 2H-Azirines and Enamides for the Synthesis
of Pyrroles. Org. Lett. 2018, 20, 1287−1290. (e) Jiang, B.; Li, Q.-Y.;
Tu, S.-J.; Li, G. Three-Component Domino Reactions for Selective
Formation of Indeno[1,2-b]indole Derivatives. Org. Lett. 2012, 14,
5210−5213. (f) Zhang, F.; Qin, Z.; Kong, K.; Zhao, Y.; Liu, Y.; Li, Y.
Metal/Benzoyl Peroxide (BPO)-Controlled Chemoselective Cyclo-
isomerization of (o-Alkynyl)phenyl Enaminones: Synthesis of α-
Naphthylamines and Indeno[1,2-c]pyrrolones. Org. Lett. 2016, 18,
5150−5153.
(19) CCDC 2076610 contains the crystallographic data for 3ag.
(20) (a) Sun, M.; Chen, W.; Xia, X.; Shen, G.; Ma, Y.; Yang, J.; Ding,
H.; Wang, Z. Palladium-Catalyzed Tandem Dehydrogenative [4 + 2]
Annulation of Terminal Olefins with N-Sulfonyl Amides via C-H
Activations. Org. Lett. 2020, 22, 3229−3233. (b) Chen, S.-Y.; Sahoo,
S. K.; Huang, C.-L.; Chan, T.-H.; Cheng, Y.-J. Pd(II)-Catalyzed
Direct Dehydrogenative Mono- and Diolefination of Selenophenes.
Org. Lett. 2020, 22, 2318−2322. (c) Chen, Y.-H.; Shao, N.-Q.; Li, C.;
Wang, D.-H. Synthesis of NH-Free 1,4-Dihydroisoquinoline-3(2H)-
ones via Pd-Catalyzed C-H Olefination Using Polyfluorosulfinyl as
the Auxiliary Group. Org. Lett. 2020, 22, 5880−5884. (d) Dou, Y.;
Kenry; Liu, J.; Jiang, J.; Zhu, Q. Late-Stage Direct o-Alkenylation of
Phenols by PdII-Catalyzed C-H Functionalization. Chem. - Eur. J.
2019, 25, 6896−6901. (e) Richa; Kumar, R.; Zhang, X.; Su, W. Direct
remote δ-C(sp2)-H olefination of β-aryl-substituted aliphatic
aldehydes via palladium/enamine co-catalysis. Org. Chem. Front.
2020, 7, 2965−2974. (f) Manna, M. K.; Hossian, A.; Jana, R. Merging
C-H Activation and Alkene Difunctionalization at Room Temper-
ature: A Palladium-Catalyzed Divergent Synthesis of Indoles and
Indolines. Org. Lett. 2015, 17, 672−675.
(14) For selected reviews and examples, see: (a) Manikandan, R.;
Jeganmohan, M. Recent advances in the ruthenium(II)-catalyzed
chelation-assisted C-H olefination of substituted aromatics, alkenes
and heteroaromatics with alkenes via the deprotonation pathway.
Chem. Commun. 2017, 53, 8931−8947. (b) Tian, S.; Luo, T.; Zhu, Y.;
Wan, J.-P. Recent advances in the diversification of chromones and
flavones by direct C-H bond activation or functionalization. Chin.
Chem. Lett. 2020, 31, 3073−3082. (c) Zhang, Z.; Tanaka, K.; Yu, J.-Q.
Remote site-selective C-H activation directed by a catalytic bifunc-
tional template. Nature 2017, 543, 538−542. (d) Grimster, N. P.;
Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J Palladium-Catalyzed
Intermolecular Alkenylation of Indoles by Solvent-Controlled
Regioselective C-H Functionalization. Angew. Chem., Int. Ed. 2005,
44, 3125−3129. (e) Cho, S. H.; Hwang, S. J.; Chang, S. Palladium-
Catalyzed C-H Functionalization of Pyridine N-Oxides: Highly
Selective Alkenylation and Direct Arylation with Unactivated Arenes.
J. Am. Chem. Soc. 2008, 130, 9254−9256. (f) Fu, L.; Xu, Z.; Wan, J.-
P.; Liu, Y. The Domino Chromone Annulation and a Transient
Halogenation-Mediated C-H Alkenylation toward 3-Vinyl Chro-
mones. Org. Lett. 2020, 22, 9518−9523.
(15) For reviews, see: (a) Li, X.-B.; Xin, Z.-K.; Xia, S.-G.; Gao, X.-Y.;
Tung, C.-H.; Wu, L.-Z. Semiconductor nanocrystals for small
molecule activation via artificial photosynthesis. Chem. Soc. Rev.
2020, 49, 9028−9056. (b) Wang, H.; Gao, X.; Lv, Z.; Abdelilah, T.;
Lei, A. Recent Advances in Oxidative R1-H/R2-H Cross-Coupling
with Hydrogen Evolution via Photo-/Electrochemistry. Chem. Rev.
2019, 119, 6769−6787. (c) Liu, Q.; Wu, L. Recent advances in
visible-light-driven organic reactions. Nat. Sci. Rev. 2017, 4, 359−380.
(16) (a) Michlik, S.; Kempe, R. A sustainable catalytic pyrrole
synthesis. Nat. Chem. 2013, 5, 140−144. (b) Daw, P.; Chakraborty,
S.; Garg, J. A.; Ben-David, Y.; Milstein, D. Direct Synthesis of Pyrroles
by Dehydrogenative Coupling of Diols and Amines Catalyzed by
Cobalt Pincer Complexes. Angew. Chem., Int. Ed. 2016, 55, 14373−
14377. (c) Zhang, M.; Fang, X.; Neumann, H.; Beller, M. General and
Regioselective Synthesis of Pyrroles via Ruthenium-Catalyzed Multi-
component Reactions. J. Am. Chem. Soc. 2013, 135, 11384−11388.
(d) Srimani, D.; Ben-David, Y.; Milstein, D. Direct Synthesis of
Pyrroles by Dehydrogenative Coupling of β-Aminoalcohols with
Secondary Alcohols Catalyzed by Ruthenium Pincer Complexes.
Angew. Chem., Int. Ed. 2013, 52, 4012−4015. (e) Qu, S.; Dang, Y.;
Song, C.; Wen, M.; Huang, K.-W.; Wang, Z.-X. Catalytic Mechanisms
of Direct Pyrrole Synthesis via Dehydrogenative Coupling Mediated
by PNP-Ir or PNN-Ru Pincer Complexes: Crucial Role of Proton-
Transfer Shuttles in the PNP-Ir System. J. Am. Chem. Soc. 2014, 136,
4974−4991.
(17) (a) Yu, Q.; Liu, Y.; Wan, J.-P. Transition metal-free synthesis of
3-trifluoromethyl chromones via tandem C-H trifluoromethylation
and chromone annulation of enaminones. Org. Chem. Front. 2020, 7,
2770−2775. (b) Zhang, B.; Liu, D.; Sun, Y.; Zhang, Y.; Feng, J.; Yu, F.
Preparation of Thiazole-2-thiones through TBPB-Promoted Oxidative
Cascade Cyclization of Enaminones with Elemental Sulfur. Org. Lett.
2021, 23, 3076. (c) Chandran, R.; Pise, A.; Shah, S. K.; Rahul, D.;
Suman, V.; Tiwari, N. Copper-Catalyzed Thiolation of Terminal
Alkynes Employing Thiocyanate as the Sulfur Source Leading to
4367
https://doi.org/10.1021/acs.orglett.1c01301
Org. Lett. 2021, 23, 4363−4367