Synthesis of 2,2,5-Trisubstituted 2 H-Pyrroles and 2,3,5-Trisubstituted 1 H-Pyrroles by Ligand-Controlled Site-Selective Dearomative C2-Arylation and Direct C3-Arylation

Article abstract of DOI:10.1021/acs.orglett.9b02559

Palladium-catalyzed site-selective dearomative C2-arylation of 2,5-diaryl-1H-pyrroles with aryl chlorides was accomplished, and a series of 2,2,5-triaryl-2H-pyrroles were synthesized. In addition, the site selectivity of the reaction was switched by simply changing the ligand, and the direct C3-arylated 2,3,5-triaryl-1H-pyrroles were prepared. The obtained 2,2,5-triaryl-2H-pyrroles could be further transformed into 2,2,5,5-tetraarylpyrrolidines.

Full text of DOI:10.1021/acs.orglett.9b02559

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of 2,2,5-Trisubstituted 2H‑Pyrroles and 2,3,5-
Trisubstituted 1H‑Pyrroles by Ligand-Controlled Site-Selective
Dearomative C2-Arylation and Direct C3-Arylation
Miyuki Yamaguchi, Sakiko Fujiwara, and Kei Manabe*
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
S
* Supporting Information
ABSTRACT: Palladium-catalyzed site-selective dearomative
C2-arylation of 2,5-diaryl-1H-pyrroles with aryl chlorides was
accomplished, and a series of 2,2,5-triaryl-2H-pyrroles were
synthesized. In addition, the site selectivity of the reaction was
switched by simply changing the ligand, and the direct C3-
arylated 2,3,5-triaryl-1H-pyrroles were prepared. The obtained
2,2,5-triaryl-2H-pyrroles could be further transformed into
2,2,5,5-tetraarylpyrrolidines.
Scheme 1. Synthesis of Trisubstituted Pyrroles by Pd-
Catalyzed Arylation
ultisubstituted pyrroles are key structural motifs that are
Moften found in biologically active natural products and
pharmaceuticals.1 They are also widely used in materials
chemistry applications.2 Among them, multisubstituted 2H-
pyrroles are of particular interest because of their unique
structural architecture and use as precursors for the synthesis
of related heterocycles such as 1-pyrrolines and pyrrolidines.
While several efforts have been devoted to the development of
synthetic methods for the preparation of multisubstituted 2H-
pyrroles,3 synthesis of compound libraries of this class remains
a challenge. For example, reports on the synthesis of 2,2,5-
triaryl-2H-pyrroles are rather limited4 and typically involve
approaches such the rearrangement and condensation of
Reissert compounds,4a addition of imines to alkynyl Fischer
carbene complexes followed by cyclization,4b,c,e and the
photochemical cyclization of chromium−imine−carbene com-
plexes with alkenes.4d
The preparation of 2H-pyrroles by the transition metal-
catalyzed dearomatization of 1H-pyrroles has recently attracted
significant attention.5 However, reports on dearomative
arylation are sparse, and such intramolecular5f and intermole-
Overall, effective methods for the preparation of 2,2,5-triaryl-
2H-pyrroles by dearomative arylation have not been reported.
Site-selective direct C−H arylation is a powerful tool for the
introduction of aryl groups.6 While several methods for the
site-selective direct C−H arylation of 1H-pyrroles have been
reported, the substrate scope and the catalyst- and ligand-
controlled selectivities of these methodologies are limited.6a
We have been interested in this area and have previously
reported the development of dihydroxyterphenylphosphine
(DHTP) ligands and the use of the Pd−DHTP catalyst for
ligand-controlled site-selective reactions.7 Importantly, C3-
cular5a arylations have been reported only once. Polak and
́
Tobrman reported the palladium-catalyzed intermolecular
dearomative C2-arylations of 2,5-dimethyl-1H-pyrrole and 2-
methyl-5-phenyl-1H-pyrrole (Scheme 1A).5a In this approach,
the deprotonation of pyrroles with n-butyllithium followed by
palladium−RuPhos-catalyzed arylation with aryl iodides or
bromides afforded 2,2,5-trisubstituted 2H-pyrroles. In addition,
these products underwent an acid-mediated rearrangement to
2,3,5-trisubstituted 1H-pyrroles. On the other hand, the 2,5-
diphenyl-1H-pyrrole congener afforded a low yield of the
corresponding 2,2,5-triaryl-2H-pyrrole because of facile re-
arrangement under these reaction conditions and afforded the
rearranged 2,3,5-triaryl-1H-pyrroles as the main products.
Received: July 23, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02559
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
selective direct arylation of N-unsubstituted indoles with aryl
chlorides and triflates was achieved in this study,7b in which
the use of DHTP as the ligand was found to be critical for
achieving site-selective C3 indole arylation. Furthermore, 3,3-
disubstituted indolenine was also synthesized from 3-
methylindole by dearomative arylation using this catalyst.
This success further prompted us to investigate the ligand-
controlled site-selective arylation using other heteroaromatic
compounds, and we report herein the results of our
investigation of the ligand-controlled C2-selective dearomative
arylation of 2,5-diaryl-1H-pyrroles with aryl chlorides (Scheme
1B).8 Furthermore, a switch in site selectivity was achieved by
changing the ligand, and the C3-selective direct C−H arylation
for the preparation of 2,3,5-triaryl-1H-pyrroles was achieved.
We selected 2,5-diphenylpyrrole 1 and 4-chlorotoluene 2 as
the model substrates for studying the site-selective arylation.
On the basis of our previous study,7b we chose tris-
(dibenzylideneacetone)dipalladium(0) as the palladium
source, lithium tert-butoxide as the base, and toluene as the
solvent. We began the study by screening the effects of various
phosphine ligands (Table 1) on the reaction conversion. The
reaction did not proceed at all in the absence of the ligand, and
1 was recovered completely (entry 1). While Cy-DHTP7 was
ineffective and afforded only a trace quantity of the desired
product (entry 2), RuPhos9 delivered a mixture of 2-aryl-2H-
pyrrole 3a, 3-aryl-1H-pyrroles 4a, and 5a (entry 3), and we
assumed that 3a rearranged to 4a and 5a under the reaction
conditions. Various biphenylphosphine ligands10 that were
developed by Buchwald and co-workers were tested next
(entries 4−10), and the reactions using XPhos, DavePhos, or
JohnPhos11 afforded 3a in good yields (entry 4, 7, or 9,
respectively); on the other hand, SPhos, Cy-JohnPhos, and
MePhos were less effective (entries 5, 6, and 8, respectively).
The use of BrettPhos did not afford the desired products
(entry 10). To suppress the rearrangement of 3a to 4a and 5a,
shorter reaction times (1 h) were evaluated, and as expected,
the use of XPhos and DavePhos afforded increased yields of
3a, along with reduced levels of formation of 4a and 5a
(entries 12 and 13, respectively). However, in these trials, 5−
10% of unreacted 1 was recovered. On the other hand, RuPhos
delivered a reduced yield of 3a at the shorter reaction time, and
a large amount of 1 remained unreacted (entry 11). The
reaction using JohnPhos afforded 3a in high yield and led to
the complete consumption of 1 (entry 14). Notably, further
decreasing the reaction time (0.75 h) was found to be effective
for increasing the yield of 3a (entry 15). Other phosphines
such as tricyclohexylphosphine and DPPF were not effective
for this conversion (entries 16 and 17, respectively). The use of
tri-tert-butylphosphine afforded both C2-arylated 3a and C3-
arylated 4a in ∼10% yield and proceeded in the absence of 5a
(entry 18). This result suggested the formation of 4a by the
direct arylation at the C3 position of 1, and not through the
rearrangement of 3a, and further suggested that the use of a
bulky ligand promotes direct arylation in this reaction. Thus,
we tested bulkier biphenylphosphine ligands comprising bulky
tert-butyl groups on the phosphorus atom (entries 19−23).
When tBuXPhos was used, the yield of 3a decreased
significantly, and C3-arylated 4a was obtained in good yield
along with the formation of a small amount of undesired 5a
(entry 19). When the reaction was conducted over a shorter
reaction time, 4a was obtained as the major product and the
yield of 3a remained low (entry 20). These results suggest that
the sterically hindered tBuXPhos suppresses the reaction at the
Table 1. Effect of Ligands on the Pd-Catalyzed Arylation of
2,5-Diphenylpyrrole with 4-Chlorotoluene
yield (%)
a
b
b
c
entry
ligand
no ligand
Cy-DHTP·HBF4
RuPhos
XPhos
SPhos
time (h)
3a
4a
5a
c
c
1
2
3
4
3
3
3
3
nd
trace
74
nd
nd
nd
nd
c
c
12
17
4
8
7
2
73
46
5
3
6
7
8
9
Cy-JohnPhos
DavePhos
MePhos
JohnPhos
BrettPhos
RuPhos
3
3
3
3
3
1
1
1
1
0.75
3
3
3
3
1
3
3
42
79
69
5
3
<8
<8
<10
<11
8
73
4
c
c
c
10
11
12
13
14
15
16
17
18
19
20
21
22
23
nd
nd
nd
nd
nd
c
c
39
78
83
81
91
1
XPhos
10
<4
6
3
<2
2
DavePhos
JohnPhos
JohnPhos
DPPF
4
1
c
c
nd
nd
nd
c
c
c
PCy3
1
nd
nd
P(tBu)3·HBF4
tBuXPhos
tBuXPhos
Me4tBuXPhos
Me3(OMe)tBuXPhos
11
24
24
5
14
7
12
69
66
63
28
5
2
c
nd
nd
nd
c
c
a
tBuBrettPhos
3
87
a
b
c
Isolated yield. NMR yield. Not detected.
C2 position of 1 and promotes the direct arylation at the C3
position. Use of Me4tBuXPhos14 gave 4a in good yield (entry
21). However, in the case of Me3(OMe)tBuXPhos,14 a low
yield of 4a was obtained (entry 22). Interestingly, tBuBrett-
Phos15 afforded 4a in high yield (entry 23). On the basis of
these results, we chose JohnPhos for C2-selective dearomative
arylation and tBuBrettPhos for C3-selective direct arylation.
Direct C3-arylation of 1H-pyrrole6d,12 is an attractive approach
for the rapid preparation of multisubstituted 1H-pyrroles, and
this report presents the first examples for the site-selective
direct C−H arylative preparation of 2,3,5-triaryl-1H-pyrroles13
from 2,5-diaryl-1H-pyrroles.
With the optimized conditions in hand, various 2,2,5-
trisubstituted 2H-pyrroles 3a−3v were synthesized by employ-
ing the catalyst derived from palladium and JohnPhos (Scheme
2). When 4-bromotoluene was used instead of 4-chloroto-
B
DOI: 10.1021/acs.orglett.9b02559
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Thiophene, pyridine, and quinoline moieties can also be
introduced as their corresponding chlorides for preparing 3l−
3n. The indane moiety was also successfully introduced from
its corresponding triflate to afford 3o in a high yield. Next, we
evaluated the use of various 2,5-disubstituted 1H-pyrroles in
the current reaction system,16 and the substrates carrying p-
tolyl, p-methoxyphenyl, and p-fluorophenyl groups afforded
the corresponding C2-arylated products 3p−3r, respectively, in
moderate to good yields. The polyheterocyclic 2,5-di-
(thiophen-2-yl)-1H-pyrrole successfully furnished 3s in high
yield. When 2-methyl-5-phenylpyrrole was used, the arylation
proceeded selectively at the methyl-substituted C2 position,
and 3t was obtained in high yield. In the case of 2,5-
dimethylpyrrole, reaction with 4-chloroanisole gave the desired
3u in good yield, whereas reaction with 4-chlorobenzonitrile
afforded 3v in low yield. We found that the use of XPhos or
RuPhos5a instead of JohnPhos was effective for increasing the
yield of 3v.
Scheme 2. Synthesis of 2,2,5-Trisubstituted 2H-Pyrroles
Having studied the scope of the 2,2,5-trisubstituted 2H-
pyrrole preparations, we turned attention to the preparation of
various 2,3,5-trisubstituted 1H-pyrroles by employing tBu-
BrettPhos as a ligand (Scheme 3). Reactions using 4-
chlorotoluene, 4-bromotoluene, or p-tolyl triflate proceeded
smoothly to afford C3-substituted 4a in moderate to good
yields, although 4-iodotoluene did not work. 3-Chlorotoluene
afforded the desired 4b in high yield. On the other hand, 2-
chlorotoluene delivered a low yield of a mixture of C3-arylated
4c and C2-arylated 3c. This result indicates that the steric
hindrance of the ortho substituents inhibits the selective C3-
arylation of 1. While chlorobenzene and 4-chloroanisole
afforded products 4d and 4e, respectively, in high yields, 2-
chloroanisole afforded 4f in a moderate yield. Aryl chlorides
bearing electron-withdrawing groups at the meta or para
position yielded C3-substituted products 4g−4k in moderate
to high yields. Albeit in moderate yields, heteroaryl groups
were introduced to give 4l−4n. Using the corresponding
triflate, triaryl 1H-pyrrole 4o bearing the indane moiety was
obtained in high yield. Reactions using various 2,5-diarylated
1H-pyrroles afforded 4p−4r in good to high yields. While 2,5-
di(thiophen-2-yl)-1H-pyrrole gave the desired 3s, 2-methyl-5-
phenyl-1H-pyrrole furnished a mixture of both C3-arylated 4t
and C2-arylated 3t. Finally, 2,5-dimethyl-1H-pyrrole was also
arylated selectively at the C3 position to afford 4v in moderate
yield. Although we attempted arylation of 2,3,5-triphenyl-1H-
pyrrole, the reaction failed and only trace amounts of the
tetraarylated products were obtained (Scheme S2).
a
Reactions were conducted on a 0.25 mmol scale. Isolated yields are
b
c
d
e
shown. On a 1 mmol scale. Three hours. Six hours. 2,5-
Dimethylpyrrole (1.5 equiv), chloroarene (1 equiv), tBuOLi (3.5
equiv). Twelve hours. XPhos. RuPhos.
f
g
h
Having studied the reaction extensively during the
optimization and the evaluation of the scope, we propose a
catalytic cycle, as shown in Scheme 4. First, oxidative addition
of the aryl chloride or triflate onto Pd leads to the formation of
intermediate A, and than selective C2- or C3-palladation
occurs to form intermediate B. Finally, reductive elimination,
followed by deprotonation for C3-arylation, affords the desired
product. On the basis of the ligand screening results and
substrate scope evaluations, we assume that the site selectivity
is controlled by the bulkiness of the ligands and not by
substrates. Compared to Pd−JohnPhos, complexes of Pd and
the bulky tBuBrettPhos are much more sterically hindered, and
thus, arylation at the less sterically hindered C3 position
proceeds preferentially.
luene, the arylation proceeded selectively at the C2 position
and afforded 3a, albeit in a lower yield. Interestingly, the
reaction with 4-iodotoluene did not proceed. To our delight,
the use of p-tolyl triflate afforded 3a in good yield. While 3-
chlorotoluene furnished the desired 3b in good yield,
chlorobenzene and 4-chloroanisole afforded the corresponding
products 3d and 3e, respectively, in high yields. On the
contrary, the ortho-substituted substrates 2-chlorotoluene and
2-chloroanisole delivered 3c and 3f, respectively, in lower
yields in comparison to those of their para-substituted
counterparts. These results suggest that the steric hindrance
of the substituents at the ortho position has a significant effect
on the reactivity in this system. Next, reactions using aryl
chlorides bearing electron-withdrawing groups at meta or para
positions were evaluated, and the corresponding C2-arylated
products 3g−3k were obtained in moderate to high yields.
To demonstrate the utility of the prepared 2,2,5-triaryl-2H-
pyrroles 3, 2,2,5-triphenyl-2H-pyrrole 3d was transformed into
the highly sterically hindered secondary amine 2,2,5,5-
C
DOI: 10.1021/acs.orglett.9b02559
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Synthesis of 2,3,5-Trisubstituted 1H-Pyrroles
Scheme 4. Proposed Catalytic Cycle
Scheme 5. Transformation of 2,2,5-Triphenyl-2H-Pyrrole
into 2,2,5,5-Tetraphenylpyrrolidine
of a 2,2,5-triaryl-2H-pyrrole afforded 2,2,5,5-tetraphenylpyrro-
lidine for the first time. Further progress, including the
asymmetric dearomative arylation using a chiral catalyst and
the site-selective arylation of asymmetrically substituted 1H-
pyrroles, will also provide powerful tools for obtaining a wide
range of multiarylated 2H- and 1H-pyrroles and their
derivatives from simple 1H-pyrroles.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02559.
Experimental procedures, spectroscopic data, and NMR
spectra of all products (PDF)
AUTHOR INFORMATION
■
a
Corresponding Author
*E-mail: manabe@u-shizuoka-ken.ac.jp.
ORCID
Reactions were conducted on a 0.25 mmol scale. Isolated yields are
b
c
d
e
shown. On a 1 mmol scale. Three hours. Six hours. Nine hours.
f
g
Twenty-four hours. 2,5-Dimethylpyrrole (1.5 equiv), 4-chloroben-
zonitrile (1 equiv), tBuOLi (3.5 equiv), 12 h.
Kei Manabe: 0000-0002-9759-1526
Notes
tetraphenylpyrrolidine 7 (Scheme 5) in a two-step process.
Hydrogenation3c of 3d afforded the trisubstituted 2,2,5-
triphenyl-3,4-dihydro-2H-pyrrole 6 in moderate yield, which
was then reacted with phenyllithium to afford the desired
2,2,5,5-tetraphenylpyrrolidine 7 in good yield, which repre-
sents the first synthesis of this molecule.
In summary, the ligand-controlled site-selective dearomative
C2-arylation of 2,5-diaryl-1H-pyrroles was established, and a
variety of 2,2,5-triaryl-2H-pyrroles were synthesized. With a
simple change in the ligand, the site selectivity of this reaction
can be easily switched, and various 2,3,5-triaryl-1H-pyrroles
were obtained by direct C3-arylation. Further transformation
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partially supported by JSPS KAKENHI (Grants
15H04634 and 17K08214), the Hamamatsu Foundation for
Science and Technology Promotion, and the Platform Project
for Supporting Drug Discovery and Life Science Research
[Basis for Supporting Innovative Drug Discovery and Life
Science Research (BINDS)] of the Japan Agency for Medical
Research and Development (AMED).
D
DOI: 10.1021/acs.orglett.9b02559
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Organic Letters
Letter
Pyrroles. Org. Lett. 2017, 19, 4608−4611. (b) Zhuo, C.-X.; Cheng,
Q.; Liu, W.−B.; Zhao, Q.; You, S.-L. Enantioselective Synthesis of
Pyrrole-Based Spiro- and Polycyclic Derivatives by Iridium-Catalyzed
Asymmetric Allylic Dearomatization and Controllable Migration
Reactions. Angew. Chem., Int. Ed. 2015, 54, 8475−8479. (c) Zhou,
Y.; Zhuo, C.-X.; Gu, Q.; You, S.-L. Intermolecular Dearomatization
Reaction of Pyrroles Promoted by Silica Gel. Adv. Synth. Catal. 2015,
357, 912−916. (d) Zhuo, C.-X.; Zhou, Y.; You, S.-L. Highly Regio-
and Enantioselective Synthesis of Polysubstituted 2H-Pyrroles via Pd-
Catalyzed Intermolecular Asymmetric Allylic Dearomatization of
Pyrroles. J. Am. Chem. Soc. 2014, 136, 6590−6593. (e) Zheng, C.;
Zhuo, C.-X.; You, S.-L. Mechanistic Insights into the Pd-Catalyzed
Intermolecular Asymmetric Allylic Dearomatization of Multisubsti-
tuted Pyrroles: Understanding the Remarkable Regio- and Enantio-
selectivity. J. Am. Chem. Soc. 2014, 136, 16251−16259. (f) Wu, K.-J.;
Dai, L.-X.; You, S.-L. Palladium(0)-Catalyzed Intramolecular
Dearomative Arylation of Pyrroles. Chem. Commun. 2013, 49,
8620−8622. (g) Zhuo, C.-X.; Liu, W.-B.; Wu, Q.-F.; You, S.-L.
Asymmetric Dearomatization of Pyrroles via Ir-Catalyzed Allylic
Substitution Reaction: Enantioselective Synthesis of Spiro-2H-
Pyrroles. Chem. Sci. 2012, 3, 205−208. For another type of
intramolecular dearomative arylation of pyrrole derivatives, see:
(h) Yang, P.; You, S.-L. Palladium-Catalyzed Asymmetric Intra-
molecular Dearomative Heck Reaction of Pyrrole Derivatives. Org.
Lett. 2018, 20, 7684−7688.
REFERENCES
■
(1) For recent reviews, see: (a) Gholap, S. S. Pyrrole: An Emerging
Scaffold for Construction of Valuable Therapeutic Agents. Eur. J. Med.
Chem. 2016, 110, 13−31. (b) Domagala, A.; Jarosz, T.; Lapkowski, M.
Living on Pyrrolic Foundations − Advances in Natural and Artificial
Bioactive Pyrrole Derivatives. Eur. J. Med. Chem. 2015, 100, 176−187.
(c) Bhardwaj, V.; Gumber, D.; Abbot, V.; Dhiman, S.; Sharma, P.
Pyrrole: A Resourceful Small Molecule in Key Medicinal Hetero-
aromatics. RSC Adv. 2015, 5, 15233−15266. (d) Wang, X.; Ma, Z.;
Wang, X.; De, S.; Ma, Y.; Chen, C. Dimeric Pyrrole−Imidazole
Alkaloids: Synthetic Approaches and Biosynthetic Hypotheses. Chem.
Commun. 2014, 50, 8628−8639. (e) Young, I. S.; Thornton, P. D.;
Thompson, A. Synthesis of Natural Products Containing the Pyrrolic
Ring. Nat. Prod. Rep. 2010, 27, 1801−1839. (f) Fan, H.; Peng, J.;
Hamann, M. T.; Hu, J.-F. Lamellarins and Related Pyrrole-Derived
Alkaloids from Marine Organisms. Chem. Rev. 2008, 108, 264−287.
(2) For recent reviews, see: (a) Krzeszewski, M.; Gryko, D.; Gryko,
D. T. The Tetraarylpyrrolo[3,2-b]pyrrolesFrom Serendipitous
Discovery to Promising Heterocyclic Optoelectronic Materials. Acc.
Chem. Res. 2017, 50, 2334−2345. (b) Rambo, B. M.; Sessler, J. L.
Oligopyrrole Macrocycles: Receptors and Chemosensors for Poten-
tially Hazardous Materials. Chem. - Eur. J. 2011, 17, 4946−4959.
(3) For recent reviews, see: (a) Patterson, J. M. Recent Synthetic
Methods for Pyrroles and Pyrrolenines (2H- or 3H-Pyrroles).
Synthesis 1976, 1976, 281−304. (b) Sammes, M. P.; Katritzky, A.
R. The 2H- and 3H-Pyrroles. Adv. Heterocycl. Chem. 1982, 32, 233−
284. Selected examples: (c) Shimbayashi, T.; Matsushita, G.; Nanya,
A.; Eguchi, A.; Okamoto, K.; Ohe, K. Divergent Catalytic Approach
from Cyclic Oxime Esters to Nitrogen-Containing Heterocycles with
Group 9 Metal Catalysts. ACS Catal. 2018, 8, 7773−7780.
(d) Koetzner, L.; Leutzsch, M.; Sievers, S.; Patil, S.; Waldmann, H.;
Zheng, Y.; Thiel, W.; List, B. The Organocatalytic Approach to
Enantiopure 2H- and 3H-Pyrroles: Inhibitors of the Hedgehog
Signaling Pathway. Angew. Chem., Int. Ed. 2016, 55, 7693−7697.
(6) For reviews, see: (a) Tiwari, V. K.; Kapur, M. Catalyst-
Controlled Positional-Selectivity in C−H Functionalizations. Org.
Biomol. Chem. 2019, 17, 1007−1026. (b) Ping, L.; Chung, D. S.;
Bouffard, J.; Lee, S.-g. Transition Metal-Catalyzed Site- and Regio-
Divergent C−H Bond Functionalization. Chem. Soc. Rev. 2017, 46,
4299−4328. (c) Rossi, R.; Lessi, M.; Manzini, C.; Marianetti, G.;
Bellina, F. Achievement of Regioselectivity in Transition Metal-
Catalyzed Direct C−H (Hetero)Arylation Reactions of Heteroarenes
with One Heteroatom through the Use of Removable Protecting/
Blocking Substituents or Traceless Directing Groups. Tetrahedron
2016, 72, 1795−1837. (d) Neufeldt, S. R.; Sanford, M. S. Controlling
Site Selectivity in Palladium-Catalyzed C−H Bond Functionalization.
Acc. Chem. Res. 2012, 45, 936−946. (e) Roger, J.; Gottumukkala, A.
L.; Doucet, H. Palladium-Catalyzed C3 or C4 Direct Arylation of
Heteroaromatic Compounds with Aryl Halides by C−H Bond
Activation. ChemCatChem 2010, 2, 20−40. (f) Ackermann, L.;
Vicente, R.; Kapdi, A. R. Transition-Metal-Catalyzed Direct Arylation
of (Hetero)arenes by C−H Bond Cleavage. Angew. Chem., Int. Ed.
2009, 48, 9792−9826. (g) Fairlamb, I. J. S. Regioselective (Site-
Selective) Functionalisation of Unsaturated Halogenated Nitrogen,
Oxygen and Sulfur Heterocycles by Pd-Catalysed Cross-Couplings
and Direct Arylation Processes. Chem. Soc. Rev. 2007, 36, 1036.
(7) (a) Ishikawa, S.; Manabe, K. DHTP Ligands for the Highly
Ortho-Selective, Palladium-Catalyzed Cross-Coupling of Dihaloar-
enes with Grignard Reagents: A Conformational Approach for
Catalyst Improvement. Angew. Chem., Int. Ed. 2010, 49, 772−775.
(b) Yamaguchi, M.; Suzuki, K.; Sato, Y.; Manabe, K. Palladium-
Catalyzed Direct C3-Selective Arylation of N-Unsubstituted Indoles
with Aryl Chlorides and Triflates. Org. Lett. 2017, 19, 5388−5391.
(8) For arylation of 1H-pyrrole with aryl chlorides, see: (a) Yigit, B.;
(e) Soret, A.; Muller, C.; Guillot, R.; Blanco, L.; Deloisy, S. Short and
̈
Efficient Synthesis of 2H-Pyrroles from 7-Oxanorbornadiene De-
rivatives. Tetrahedron 2011, 67, 698−705. (f) Ghavtadze, N.;
̈
̈
Frohlich, R.; Wurthwein, E.-U. 2H-Pyrrole Derivatives from an
Aza−Nazarov Reaction Cascade Involving Indole as the Neutral
Leaving Group. Eur. J. Org. Chem. 2008, 2008, 3656−3667.
(g) Cheruku, S. R.; Padmanilayam, M. P.; Vennerstrom, J. L.
Synthesis of 2H-Pyrroles by Treatment of Pyrrolidines with DDQ.
Tetrahedron Lett. 2003, 44, 3701−3703. (h) Chahma, M.; Combellas,
́
C.; Thiebault, A. Delocalized Nitrogen Carbanions in SRN1
Reactions. J. Org. Chem. 1995, 60, 8015−8022. (i) Sammes, M. P.
Physical and Theoretical Aspects, Synthesis, and Chemical Reactivity
of 2H- and 3H-Pyrroles. In Chemistry of Heterocyclic Compounds;
Jones, R. A., Ed.; John Wiley & Sons, 1990; Vol. 48, Chapter 4, pp
549−728. (j) Joseph, S. P.; Dhar, D. N. Reaction of Chlorosulfonyl
Isocyanate with Nitrones: An Efficient Method for the Synthesis of
Cyclic Enamides and 2H-Pyrroles. Tetrahedron 1988, 44, 5209−5214.
(4) (a) Liao, T.-K.; McEwen, W. E. Acylation of a Carbonium Ion
by the Action of a Reissert Compound. J. Org. Chem. 1961, 26, 5257−
5258. (b) Funke, F.; Duetsch, M.; Stein, F.; Noltemeyer, M.; de
Meijere, A. Michael Addition of Imines to Alkynylcarbene Complexes
with Subsequent Intramolecular Cyclization − An Efficient Three-
Step Synthesis of 2H-Pyrroles. Chem. Ber. 1994, 127, 911−920.
(c) Campos, P. J.; Sampedro, D.; Rodriguez, M. A. Photochemistry of
Imine−Group VI Carbene Complexes: Novel Reactivity Involving a
Cyclopentannulation Reaction. Organometallics 2000, 19, 3082−3084.
(d) Campos, P. J.; Sampedro, D.; Rodríguez, M. A. Irradiation of
Imine−Group VI Carbene Complexes in the Presence of Alkynes: A
Theoretical and Experimental Study. J. Org. Chem. 2003, 68, 4674−
̈
Gurbuz, N.; Yigit, M.; Dagdeviren, Z.; Ozdemir, I. Palladium(II) N-
Heterocyclic Carbene Complexes as Catalysts for the Direct Arylation
of Pyrrole Derivatives with Aryl Chlorides. Inorg. Chim. Acta 2017,
̈
̇
̈
̆ ̆
465, 44−49. (b) Ozdemir, I.; Gurbuz, N.; Kaloglu, N.; Dogan, O.;
̈ ̈
̆
Kaloglu, M.; Bruneau, C.; Doucet, H. N-Heterocyclic Carbene−
Palladium Catalysts for the Direct Arylation of Pyrrole Derivatives
with Aryl Chlorides. Beilstein J. Org. Chem. 2013, 9, 303−312.
(c) Roy, D.; Mom, S.; Royer, S.; Lucas, D.; Hierso, J.-C.; Doucet, H.
Palladium-Catalyzed Direct Arylation of Heteroaromatics with
Activated Aryl Chlorides Using a Sterically Relieved Ferrocenyl-
Diphosphane. ACS Catal. 2012, 2, 1033−1041. (d) Nadres, E. T.;
Lazareva, A.; Daugulis, O. Palladium-Catalyzed Indole, Pyrrole, and
Furan Arylation by Aryl Chlorides. J. Org. Chem. 2011, 76, 471−483.
(e) Roy, D.; Mom, S.; Beauperin, M.; Doucet, H.; Hierso, J.-C. A
́
4683. (e) Gonzalez, H. F.; Blanco-Lomas, M.; Rivado-Casas, L.;
Rodríguez, M. A.; Campos, P. J.; Sampedro, D. Addition of Oxime
Derivatives to Alkynyl Fischer Carbene Complexes. Organometallics
2012, 31, 6572−6581.
́
(5) (a) Polak, P.; Tobrman, T. Dearomatization Strategy for the
Synthesis of Arylated 2H-Pyrroles and 2,3,5-Trisubstituted 1H-
E
DOI: 10.1021/acs.orglett.9b02559
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Versatile Palladium/Triphosphane System for Direct Arylation of
Heteroarenes with Chloroarenes at Low Catalyst Loading. Angew.
Chem., Int. Ed. 2010, 49, 6650−6654.
(9) Milne, J. E.; Buchwald, S. L. An Extremely Active Catalyst for the
Negishi Cross-Coupling Reaction. J. Am. Chem. Soc. 2004, 126,
13028−13032.
(10) Surry, D. S.; Buchwald, S. L. Biaryl Phosphane Ligands in
Palladium-Catalyzed Amination. Angew. Chem., Int. Ed. 2008, 47,
6338−6361.
(11) Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J.
P.; Buchwald, S. L. Novel Electron-Rich Bulky Phosphine Ligands
Facilitate the Palladium-Catalyzed Preparation of Diaryl Ethers. J. Am.
Chem. Soc. 1999, 121, 4369−4378.
(12) (a) Ueda, K.; Amaike, K.; Maceiczyk, R. M.; Itami, K.;
Yamaguchi, J. β-Selective C−H Arylation of Pyrroles Leading to
Concise Syntheses of Lamellarins C and I. J. Am. Chem. Soc. 2014,
136, 13226−13232. (b) Yamaguchi, A. D.; Mandal, D.; Yamaguchi, J.;
Itami, K. Oxidative C−H/C−H Coupling of Azine and Indole/
Pyrrole Nuclei: Palladium Catalysis and Synthesis of Eudistomin U.
Chem. Lett. 2011, 40, 555−557. (c) Ackermann, L.; Dell’Acqua, M.;
Fenner, S.; Vicente, R.; Sandmann, R. Metal-Free Direct Arylations of
Indoles and Pyrroles with Diaryliodonium Salts. Org. Lett. 2011, 13,
2358−2360. (d) Wagner, A. M.; Sanford, M. S. Palladium-Catalyzed
C−H Arylation of 2,5-Substituted Pyrroles. Org. Lett. 2011, 13, 288−
291. (e) Fall, Y.; Doucet, H.; Santelli, M. Palladium-Catalysed Direct
3- or 4-Arylation of 2,5-Disubstituted Pyrrole Derivatives: An
Economically and Environmentally Attractive Procedure. ChemSu-
sChem 2009, 2, 153−157.
(13) Recent examples of 2,3,5-triaryl-1H-pyrrole synthesis: (a) Mis-
hra, P. K.; Verma, S.; Kumar, M.; Verma, A. K. Base-Mediated Direct
Transformation of N-Propargylamines into 2,3,5-Trisubstituted 1H-
Pyrroles. Org. Lett. 2018, 20, 7182−7185. (b) 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. (c) Chan, C.-M.; Zhou, Z.; Yu, W.-Y.
Rhodium-Catalyzed Oxidative Cycloaddition of N-tert-Butoxycarbo-
nylhydrazones with Alkynes for the Synthesis of Functionalized
Pyrroles via C(sp3)−H Bond Functionalization. Adv. Synth. Catal.
2016, 358, 4067−4074. (d) Donthiri, R. R.; Samanta, S.; Adimurthy,
S. Copper-Catalyzed C(sp3)−H Functionalization of Ketones with
Vinyl Azides: Synthesis of Substituted-1H-Pyrroles. Org. Biomol.
Chem. 2015, 13, 10113−10116. (e) Xu, Y.-H.; He, T.; Zhang, Q.-C.;
Loh, T.-P. Synthesis of Multi-Substituted Pyrroles Using Enamides
and Alkynes Catalyzed by Pd(OAc)2 with Molecular Oxygen as an
Oxidant. Chem. Commun. 2014, 50, 2784−2786. (f) Shen, J.; Cheng,
G.; Cui, X. One pot” Regiospecific Synthesis of Polysubstituted
Pyrroles from Benzylamines and Ynones under Metal Free
Conditions. Chem. Commun. 2013, 49, 10641−10643. (g) Zhang,
M.; Neumann, H.; Beller, M. Selective Ruthenium-Catalyzed Three-
Component Synthesis of Pyrroles. Angew. Chem., Int. Ed. 2013, 52,
597−601.
(14) Ueda, S.; Ali, S.; Fors, B. P.; Buchwald, S. L. Me3(OMe)-
tBuXPhos: A Surrogate Ligand for Me4tBuXPhos in Palladium-
Catalyzed C−N and C−O Bond-Forming Reactions. J. Org. Chem.
2012, 77, 2543−2547.
(15) Fors, B. P.; Buchwald, S. L. Pd-Catalyzed Conversion of Aryl
Chlorides, Triflates, and Nonaflates to Nitroaromatics. J. Am. Chem.
Soc. 2009, 131, 12898−12899.
(16) The reaction of unsubstituted 1H-pyrrole gave the N-arylated
compound as the major product. See Scheme S1.
F
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