Pd-catalyzed imine-directed intramolecular C–N bond formation through C(sp3)–H activation: An efficient approach to multisubstituted pyrroles

Article abstract of DOI:10.1016/j.tetlet.2020.151887

An atom-economic approach to synthesize 1,2,4-trisubstituted pyrroles through palladium-catalyzed imine-directed intramolecular C(sp³)–H amination reaction has been developed. The imine group acts as a directing group as well as an intramolecular nucleophile for the first time in intramolecular C–N bonds formation reactions.

Full text of DOI:10.1016/j.tetlet.2020.151887

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Pd-catalyzed imine-directed intramolecular CAN bond formation
through C(sp3)AH activation: An efficient approach to multisubstituted
pyrroles
a,b,
Ting Yu a,b, Qiang Zhu a,b,c, , Shuang Luo
⇑
⇑
a State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou 510530, China
b University of Chinese Academy of Sciences, No. 19(A) Yuquan Road, Shijingshan District, Beijing 100049, China
c College of Chemistry and Materials, Guangxi Key Laboratory of Natural Polymer Chemistry and Physics, Nanning Normal University, Nanning 530001, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An atom-economic approach to synthesize 1,2,4-trisubstituted pyrroles through palladium-catalyzed
imine-directed intramolecular C(sp3)AH amination reaction has been developed. The imine group acts
as a directing group as well as an intramolecular nucleophile for the first time in intramolecular CAN
bonds formation reactions.
Received 23 January 2020
Revised 23 March 2020
Accepted 27 March 2020
Available online xxxx
Ó 2020 Published by Elsevier Ltd.
Keywords:
Multisubstituted pyrroles
Palladium-catalyzed reactions
C(sp3)AH amination
CAN bond formation
Introduction
Over the past few decades, an immense effort has been made
in transition metal-catalyzed direct CAN bonds formation from
Multisubstituted pyrroles are key structural units in numerous
natural products [1,2]. They have also been widely used for the
synthesis of bioactive molecules, pharmaceuticals and functional
materials [3–5]. Therefore, a myriad of synthetic methods have
been developed for the construction of multisubstituted pyrroles,
including palladium-catalyzed arylation of 2,4-disubstituted pyr-
roles [6], condensation/cyclization of b-formyl aryl ketones [7,8],
CAH bonds [12–14], for this approach was considered as a step-
efficient and environmentally benign alternative to the traditional
CAN bonds formation methods. However, due to the ubiquity and
robustness of CAH bonds, it is still a challenge to develop highly
efficient catalytic system with excellent region- and chemo-selec-
tivity. A general approach to solve this problem is the use of a
directing group (DG) strategy to allow selective CAH bond activa-
tion by the localized transition-metal catalyst [15–19] (Scheme 1).
The intramolecular version of CAN bonds formation from CAH
bonds, in which the N atoms act as directing groups as well as
nucleophiles, provides a convenient method for the construction
of N-heterocycles with high step efficiency and atom economy
[20,21]. By using this strategy, a variety of N-containing func-
tional groups, such as amines [22,23], amides [24,25], amidines
[26], hydrazones [27,28], pyridines [29,30], have been applied in
and plenty of N-heterocyclic products have been synthesized.
However, imine has never been applied in this process. Herein,
or
c
-bromodypnones with anilines [9], gold-catalyzed hydroami-
-amino aryl ketones with phenylacetylenes
nation/cyclization of
a
[10], and palladium-catalyzed [3+2] cycloaddition of ketoimines
with alkynes [11]. Although most of these approaches are suffi-
ciently powerful, they generally involve special starting materials,
multistep procedures and preliminary preparation of some kind of
intermediates or precursors. From the point of view of atom- and
process-economical chemistry, developing an efficient and general
approach to multisubstituted pyrroles is
importance.
a subject of great
we present
a
novel palladium-catalyzed imine-directed
intramolecular CAN bond formation through allylic sp3 CAH bond
activation to synthesize multisubstituted pyrroles. In this reac-
tion, the iminyl directing group acts as an intramolecular nucle-
ophile as well.
⇑
Corresponding authors at: State Key Laboratory of Respiratory Disease,
Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences,
190 Kaiyuan Avenue, Guangzhou 510530, China.
E-mail addresses: zhu_qiang@gibh.ac.cn (Q. Zhu), luo_shuang@gibh.ac.cn
(S. Luo).
https://doi.org/10.1016/j.tetlet.2020.151887
0040-4039/Ó 2020 Published by Elsevier Ltd.
Please cite this article as: T. Yu, Q. Zhu and S. Luo, Pd-catalyzed imine-directed intramolecular CAN bond formation through C(sp3)AH activation: An effi-
cient approach to multisubstituted pyrroles, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151887

2
T. Yu et al. / Tetrahedron Letters xxx (xxxx) xxx
Scheme 1. Intramolecular CAN bond formation from CAH bond.
isolated in 75% yield under the modified conditions (entry 12,
Table 1).
With the optimal reaction conditions in hand, the substrate
Results and discussion
Initially, treatment of
a,b-unsaturated imine 3aa in the pres-
scope was then investigated as summarized in Scheme 2. Various
anilines bearing different substituents were tolerated in this reac-
tion to furnish the corresponding products in moderate to good
yields (Scheme 2), including electron-donating groups, such as
alkyl (4ab, 4ag), alkyoxyl (4ac), and electron-withdrawing groups
including halogen (4ad–4af). It should be noted that ortho-substi-
tuted aniline led to a lower yield probably due to the increased
steric hindrance (4ah). Moreover, alkyl amines also allowed for this
reaction and produced the desired products in moderate to excel-
lent yields. Primary amines such as benzyl amine (4ai), cyclohexy-
lamine (4al) and cyclopentylamine (4am) could afford the product
in 94%, 75% and 63%, respectively. The bulky tert-butylamine gave
the product in a lower yield (36%) due to the steric hindrance
(4ak). Subsequently, we further investigated the substituents
ence of Pd(OAc)2 in DMSO under an O2 atmosphere at 60 °C for
24 h afforded the desired product 4aa in 44% yield (entry 1,
Table 1). When the reaction was performed in toluene, DMF, MeCN
or THF, no reaction occurred and the imine was totally recovered
(entries 2–5, Table 1). The yield of product decreased drastically
when 2.0 equiv. of K2CO3 was added (entry 6, Table 1), while the
yield increased when a phase-transfer-catalyst was added (entries
7–9, Table 1). Tetrabutylammonium bromide (TBAB) was the best
choice of additive and the product could be obtained in 82% yield
[31]. A lower yield was obtained when 1.0 equiv. of TBAB was used
(entry 10, Table 1). Finally, 4aa could be isolated in 93% yield with
a higher temperature of 80 °C (entry 11, Table 1). Moreover, an
one-pot strategy was also conducted, starting from
a,b-unsatu-
rated ketone 1a and aniline 2a, the desired product 4aa could be
Table 1
Optimization of the reaction conditions.a
Entry
Solvent
Additive
Yield (%)b
1
2
3
DMSO
Toluene
DMF
–
–
–
44
0
0
4
5
MeCN
THF
–
–
0
0
6
7
8
9
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
K2CO3
TBAC
TBAB
TBAI
TBAB
TBAB
TBAB/PivOH
18
63
82
80
76
96(93)
80(75)
10c
11d
12d,e
a
b
c
Reaction conditions: 3aa (0.1 mmol), Pd(OAc)2 (0.01 mmol), additive (0.2 mmol), O2 balloon (1 atm), solvent (0.1 M), 60 °C, 24 h.
The yield was determined by 1H NMR analysis of the crude product using dibromomethane as an internal standard. Numbers in parentheses are isolated yields of 4aa.
TBAB = 0.1 mmol.
80 °C.
d
e
1a (0.2 mmol), 2a (0.4 mmol), Pd(OAc)2 (0.02 mmol), TBAB (0.4 mmol), PivOH (0.1 mmol), 4 Å MS (200 mg), O2 balloon (1 atm), DMSO (anhydrous, 2 mL), 80 °C, 24 h.
Please cite this article as: T. Yu, Q. Zhu and S. Luo, Pd-catalyzed imine-directed intramolecular CAN bond formation through C(sp3)AH activation: An effi-
cient approach to multisubstituted pyrroles, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151887

T. Yu et al. / Tetrahedron Letters xxx (xxxx) xxx
3
Scheme 2. Substrate scope. Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol). Pd(OAc)2 (0.02 mmol), TBAB (0.4 mmol), PivOH (0.1 mmol), 4 Å MS (200 mg), O2 balloon (1 atm),
DMSO (2 mL), 80 °C, 24 h.
effects of the
found that electron-rich
yield of product (4di), while electron-deficient substrates showed
better performance (4ci, 4ei, 4fi). Moreover, heteroaryl substituted
a
,b-unsaturated ketones on this transformation, and
,b-unsaturated ketone offered a lower
kinetic isotope effect experiments were conducted under the stan-
dard conditions (Eq. (2), Scheme 3), and the corresponding KIE
value (KH/KD = 7.8) indicated that the CAH activation step might
go through a concerted metalation deprotonation (CMD) process,
and the CAH activation might be involved in the rate-determining
step.
a
a,b-unsaturated ketone could also applied in this reaction and
afforded the product in 70% yield (4hi). Importantly, this reaction
protocol could run smoothly with unsymmetrical
ketones (4gi, 4ii, 4ji).
a,b-unsaturated
On the basis of the above-mentioned experimental results and
previous studies, a plausible mechanism was proposed (Scheme 4).
To gain preliminary insight into the reaction mechanism, we
conducted a series of deuterium labeling experiments (Scheme 3).
Initial condensation of
a,b-unsaturated ketone 1a and aniline 2a
affords ,b-unsaturated imine 3aa. Then coordination of the N
a
First, when
a
,b-unsaturated ketone 3ac was subjected to the Pd(II)/
atom in 3aa to Pd(II) generates the intermediate A. Next, activation
of the C(sp3)AH bond aided by the coordinated carboxylate
through a concerted metalation deprotonation (CMD) process
gives a six-membered palladacycle B. The coordination of the N
atom in 3aa assists the formation of a g3 coordinated palladium
CD3OD system for 24 h in the absence of oxygen, 49% deuterium
incorporation was observed at the methyl group of 3ac and 24%
deuterium incorporation was observed at the alkenyl group (Eq.
(1), Scheme 3). This result indicated that a
ladium intermediate was probably involved in the reaction. Finally,
g g
3 or 5 coordinated pal-
intermediate C or g
5 coordinated palladium intermediate D, which
Please cite this article as: T. Yu, Q. Zhu and S. Luo, Pd-catalyzed imine-directed intramolecular CAN bond formation through C(sp3)AH activation: An effi-
cient approach to multisubstituted pyrroles, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151887

4
T. Yu et al. / Tetrahedron Letters xxx (xxxx) xxx
Scheme 3. The mechanism study.
Scheme 4. Proposed mechanism.
converts to intermediate E after releasing a HOR molecule. Finally,
reductive elimination of intermediate E delivers pyrrole 4aa and
generate a Pd(0) species which can be oxidized by O2 to afford
the catalytically active Pd(II) complex for the next catalytic cycle.
atmosphere. Column chromatography was conducted with 200–
300 mesh silica gel. 1H NMR (400 MHz) and 13C NMR (125 MHz)
were registered on 400 M or 500 M spectrometers. Chemical shifts
were reported in units (ppm) by assigning TMS resonance in the 1H
spectrum as 0.00 ppm, CDCl3 resonance in the 13C spectrum as
77.0 ppm. All coupling constants (J values) were reported in Hertz
(Hz). The following abbreviations were used to describe peak split-
ting patterns when appropriate: br s = broad singlet, s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet. High resolution
mass spectra (HRMS) were obtained on an ESI-LC-MS/MS
spectrometer.
Materials and methods
General methods
All reactions dealing with air- and moisture-sensitive com-
pounds were carried out in dry reaction vessels under a nitrogen
Please cite this article as: T. Yu, Q. Zhu and S. Luo, Pd-catalyzed imine-directed intramolecular CAN bond formation through C(sp3)AH activation: An effi-
cient approach to multisubstituted pyrroles, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151887

T. Yu et al. / Tetrahedron Letters xxx (xxxx) xxx
5
General materials
Appendix A. Supplementary data
Unless otherwise noted, materials were purchased from Alfa
Aesar, and other commercial suppliers and were used as received.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.151887.
Experimental
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Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Please cite this article as: T. Yu, Q. Zhu and S. Luo, Pd-catalyzed imine-directed intramolecular CAN bond formation through C(sp3)AH activation: An effi-
cient approach to multisubstituted pyrroles, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151887