One-Pot Synthesis of N-H-Free Pyrroles from Aldehydes and Alkynes

Article abstract of DOI:10.1021/acs.orglett.1c01287

The first base-mediated intermolecular cyclization of arylaldehydes and terminal arylacetylenes for the synthesis of a wide range of pyrroles in a single step has been described. The developed methodology used commercially available starting materials and

Full text of DOI:10.1021/acs.orglett.1c01287

pubs.acs.org/OrgLett
Letter
One-Pot Synthesis of N−H-Free Pyrroles from Aldehydes and
Alkynes
#
#
Lai Chen, Jing-Qian Huo, He-Long Si, Xin-Yu Xu, Song Kou, Jianyou Mao,* and Jin-Lin Zhang*
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sı Supporting Information
ABSTRACT: The first base-mediated intermolecular cyclization of
arylaldehydes and terminal arylacetylenes for the synthesis of a wide
range of pyrroles in a single step has been described. The developed
methodology used commercially available starting materials and tolerated
a broad range of functional groups affording 2,3,5-triaryl-substituted-1H-
pyrroles with good yields (up to 92% yield) under mild conditions. The
possible mechanism was also discussed.
yrroles, among the most prevalent five-membered
selective method for one-pot aminobenzylation of aldehydes
P
heterocyclic motifs, are present in a plethora of natural
with toluenes based on tandem C−N and C−C bond
1
9
products, and as core substructures of pharmaceuticals, also
possess various bioactivities such as antifungal, antiviral,
formations (Scheme 2a). More recently, this transformation
10
has been achieved with a catalytic base. Further adaptation of
this strategy has led to a diverse array of routes to
2
antihyperlipidemic, and anticancer activities. In addition,
11
they are also broadly applied in agrochemicals and functional
functionalized heterocycles, such as 2-arylindoles, 2-azaar-
3
1
2
13
materials.
yltetrahydroquinolines, and others. The key findings
include the following: (1) The Group I main group cation−π
interactions facilitate toluene deprotonation. (2) MN(SiMe )
Accordingly, traditional routes to access pyrroles include the
4
5
Knorr and Hantzsch reactions (Scheme 1). A majority of
3
2
(
M = Li, Na, K, Cs) plays two roles: one is direct
Scheme 1. Traditional Routes to Access Pyrroles
3
deprotonation of weakly acidic C(sp )−H bonds, and the
other is condensation with benzaldehyde to in situ generate N-
(
trimethylsilyl)imines. (3) The products are of great
importance motifs. When we explored MN(SiMe ) (M =
3
2
Li, Na, K, Cs)-catalyzed addition of phenylacetylene to in situ
generated TMS-imines, we detected formation of trace amount
of pyrrole without forming propargylamine. Herein, we present
the first straightforward and practical one-pot synthesis of
2
,3,5-trisubstituted pyrroles from simple feedstocks, i.e.,
contemporary pyrrole synthesis involve transition-metal
catalyzed pyrrole functionalization reactions (transition-metals
involved), multicomponent reactions, and many others.
aldehydes and terminal alkynes (Scheme 2b). Compared
14
with previous strategies by Wan, Verma, and Cui, our
method provides a valuable alternative to synthesis of N−H
pyrroles, circumventing the need for preformed imines,
propargylamines, or functionalized ynones (Scheme 2c−e).
Also, these N−H-free pyrroles provide a handle to generate a
diverse array of N-protected pyrrole derivatives.
6
7
8
Recent progress along these lines has been remarkable, but
highly functionalized starting materials or preformed inter-
mediates are needed. Also, the stringent requirements for trace
metal contamination in bioactive compounds, however, have
driven the desire to develop transition-metal-free processes.
Consequently, the demand for efficient, straightforward, and
economical pyrrole synthesis from abundant feedstocks in the
absence of transition metals remains high.
Received: April 14, 2021
Published: May 20, 2021
We are interested in silylamide base MN(SiMe ) (M = Li,
3
2
Na, K, Cs)-mediated/catalyzed deprotonative addition reac-
3
tions with substrates possessing a weakly acidic C(sp )−H
bond. Recently, we developed a novel, efficient, and chemo-
©
2021 American Chemical Society
https://doi.org/10.1021/acs.orglett.1c01287
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Org. Lett. 2021, 23, 4348−4352

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Letter
a
Scheme 2. Base-Mediated Deprotonative Functionalization
and Base-Mediated Routes to Access Pyrroles
Table 1. Optimization of the Reaction Conditions
b
entry
base
1a:2a:base
solvent
T(°C) AY (%)
1
2
3
4
5
6
7
8
9
KN(SiMe3)2
NaN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
1:1:3
1:1:3
1:1:3
1:2:4
1:2:4
1:2:4
1:2:4
1:2:4
1:2:4
1:2:4
1:2:4
1:2:4
1:2:4
1:2:4
1:2:3
1:3:4
CPME
CPME
CPME
CPME
DME
110
110
110
110
110
110
110
110
110
110
100
80
18
10
24
43
16
0
35
28
41
47
44
<5
64
63
84
75
THF
i-Pr O
2
dioxane
PhMe
10
11
12
13
14
15
16
TBME
TBME
TBME
TBME
TBME
TBME
TBME
c
d
c
c
e
e
e
e
110
110
110
110
a
Reactions were performed on a 0.1 mmol scale in 1 mL of solvent
b
(0.1 M) for 12 h. Assay yields of 3a were determined by HPLC
c
analysis. Reactions were performed in 0.5 mL of solvent (0.2 M).
d
e
Reactions were performed in 0.2 mL of solvent (0.5 M). Isolated
yield. CPME = cyclpentyl methyl ether, DME = ethanediol dimethyl
ether, THF = tetrahydrofuran, i-Pr O = isopropyl ether, dioxane =
2
1,4-dioxane, TBME = methyl tert-butyl ether.
To initiate the optimization of the tandem reaction with
phenylacetylene 1a and benzaldehyde 2a, we examined three
different bases [KN(SiMe ) , NaN(SiMe ) , and LiN-
substituted arylaldehydes 2 was explored under the standard
conditions. In general, these transformations gave the N−H-
free pyrrole derivatives with moderate to good yields (Scheme
3). The aldehyde substrates with Cl, Br, and F atoms at the
para position afforded the corresponding pyrroles (3b−3d) in
68%, 38%, and 45% yields, respectively. The low yield of 3c
was possibly due to the decomposition of p-bromobenzalde-
hyde under our reaction conditions. The halogen-containing
pyrroles could be easily converted to further functionalized
products via cross-coupling strategy. Aromatic aldehydes
bearing electron-donating groups, such as 4-OMe, 3,4-
3
2
3 2
(
SiMe ) ] using CPME (cyclopentyl methyl ether) as solvent
3 2
at 110 °C for 12 h, affording the desired product 3a in 24%
yield with LiN(SiMe ) as the promising hit (entry 3) (Table
3
2
1
). Increasing the amount of 2a from 1 to 2 equiv and
improving the loading of LiN(SiMe ) from 3 to 4 equiv led to
3
2
an enhanced yield of 3a (43%, entry 4). Additionally, other
i
ethereal solvents (CPME vs DME, THF, Pr O, dioxane, and
2
TBME) and noncoordination toluene were also examined
under the conditions of entry 4. The reaction in TBME
exhibited the highest yield (47%, entry 10 vs entries 4−9).
Further screening revealed that decreasing the reaction
temperature from 110 to 100 °C had little effect on the
yield of 3a (entry 10 vs entry 11). When the reaction was
performed at 80 °C, a low AY of 3a was obtained (entry 10 vs
entry 12), indicating that decreasing the temperature had a
detrimental impact on the AY of 3a. Furthermore, increasing
the concentration of the reaction had little impact on the yield,
as exemplified in entries 13 (0.2 M, 64% yield) and 14 (0.5 M,
(OMe) , and 4-SMe (2e−2g), underwent these tandem
2
reactions and generated the desired products in 46−77%
yield. Besides, aromatic aldehyde with a weak electronegative
4-OCF3 substituent was also tolerated in the reaction
condictions, furnishing product 3h with 57% yield. Aldehydes
possessing a methyl group in the ortho, meta, and para position
furnished the desired products (3i−3k) smoothly in 62−83%
yield, respectively. Moreover, aldehydes containing 3,5-di-
(CH ) (2l), 4-t-Bu (2m), and 4-phenyl (2n) substituents
3
2
6
3% yield). Finally, we reoptimized the ratio of substrate 2a
and the base with TBME under the conditions of entry 13
entry 13 vs entries 15−16), which revealed significant change
reacted with phenylacetylene (1a) to form corresponding
products in 62%, 59%, and 70% yields, respectively. Among
them, product 3l was also characterized by single X-ray
diffraction. Using π-extended 1-naphthaldehyde (2o) and 2-
naphthaldehyde (2p) under the standard conditions provided
the desired product (3o, 3p) in 58% and 77% yields,
respectively. Heterocyclic compounds are present in many
agrochemicals and pharmaceuticals. Substrate containing
benzofuran heterocycle was also found to successfully engage
in this transformation, providing the corresponding pyrrole
(3q) in 53% yield. Besides, other substrates of aldehydes such
as cinnamaldehyde, N-methylpyrrole-2-carboxaldehyde, and
(
in the yield of the product 3a with entry 15 having the highest
yield (84%). Therefore, the optimized conditions employed 2
equiv of benzaldehyde (2a), 1 equiv of phenylacetylene (1a),
and 3 equiv of LiN(SiMe ) in TBME (0.2 M) at 110 °C for
3
2
1
2 h. It should be noted that 2 equiv of LiN(SiMe ) was used
3 2
to condense with benzaldhyde and eliminate via aza-Peterson
reaction to generate in situ N-(trimethylsilyl)imines.
Under the optimized conditions, the scope of the base-
mediated cyclization of phenylacetylene (1a) with various
4
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Organic Letters
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Letter
a
a
Scheme 3. Substrate Scope of Arylaldehydes
Scheme 4. Substrate Scope of Terminal Arylacetylenes
a
Reaction conditions: 1 (0.1 mmol), 2a (0.2 mmol), LiN(SiMe )
3
2
b
(
0.3 mmol), TBME (0.5 mL); isolated yield. Reaction performed at
80 °C for 3 h. Reaction performed at room temperature.
a
c
Reaction conditions: 1a (0.1 mmol), 2 (0.2 mmol), LiN(SiMe )
3
2
b
(
0.3 mmol), TBME (0.5 mL); isolated yield. Reaction performed at
c
8
0 °C. Reaction performed for 3 h.
hyde. For example, 2-thiopheneacetylene (1o) and 2-
pyridineacetylene (1p) could afford the desired products 4o
(41%) and 4p (51%). Finally, we also performed the reaction
with aliphatic terminal alkynes such as 1-cyclohexynl, cyclo-
propyl, n-Bu, but these substrates did not react with
benzaldehyde under our reaction condition with most of the
starting materials recovered (see the Supporting Information
for unsuccessful examples).
thiophene-2-carboxaldehyde were also examined, but they all
decomposed under our standard conditions. Finally, when
pivalaldehyde was employed under our standard conditions, it
provided 4,4-dimethyl-1-phenylpent-1-yn-3-ol in a 95% yield
instead of the pyrrole product (see the Supporting Information
for unsuccessful examples).
15
On the basis of the successful cyclization of phenylacetylene
On the basis of the previous reports, we have proposed a
plausible mechanism for the tandem formation of 2,3,5-triaryl-
1H-pyrroles (Figure 1). The reaction might be assumed to
start with the deprotonation of acetylene 1a under the action
of the LiN(SiMe ) followed by the addition of acetylenic
(
1a) with aromatic aldehydes above, we next examined the
scope of terminal arylacetylenes with benzaldehyde 2a
Scheme 4). Phenylacetylene possessing methyl group at the
(
para, meta, and ortho position (4a−c), and other alkyl groups
at the 4-position, such as Et (4d), n-Bu (4e), and t-Bu (4f),
exhibited good yields (70−79%). Besides, phenylacetylene
containing halogen atom on the benzene ring, including Cl in
the para, meta, and ortho positions, and Br in the para position,
exhibited good to excellent reactivity, providing products 4g−j
in 58−92% yields upon isolation, respectively. In addition,
phenylacetylene bearing electron-donating 4-OMe (4k) and 4-
3
2
9
,16
anion A to the in situ generated N-(trimethylsilyl)imines B.
This imine is formed through the aza-Peterson olefination
9
mechanism. This addition between A and B thus gives
propargylamine anion C. The intermediate C subsequently
undergoes a 1,2-anion shift to afford propargyllithium reagent
17
D, which is in equilibrium with the allenyllithium E. Then
allenyllithium E is added to another molecule of imine B to
form the intermediate F, followed by intramolecular cyclization
to provide the intermediate G. Protonation with C results in
N(Me) (4l) groups could furnish products in 66% and 53%
2
yield, respectively. Phenylacetylene with extended π-systems,
such as those derived from 4-biphenylacetylene (1m) and 2-
ethynylnaphthalene (1n) also provided products 4m (47%)
and 4n (67%). It is noteworthy that pyrroles with heteroaryl
substituents at the 3-position could be obtained from reactions
of the corresponding heterocyclic acetylenes with benzalde-
14a,18
the intermediate H.
Then the elimination of aniline from
H gives intermediate I. Finally, the intermediate I is hydrolyzed
to produce the desired pyrroles J.
To summarize, we have developed a novel method for the
synthesis of triaryl-substituted pyrroles in one step from
4
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Org. Lett. 2021, 23, 4348−4352

Organic Letters
pubs.acs.org/OrgLett
Letter
Jing-Qian Huo − College of Plant Protection, Hebei
Agricultural University, Baoding 071001, P. R. China
He-Long Si − College of Life Sciences, Hebei Agricultural
University, Baoding 071001, P. R. China
Xin-Yu Xu − Technical Institute of Fluorochemistry (TIF),
Institute of Advanced Synthesis, School of Chemistry and
Molecular Engineering, Nanjing Tech University, Nanjing
211816, P. R. China
Song Kou − College of Plant Protection, Hebei Agricultural
University, Baoding 071001, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01287
Author Contributions
#
L. Chen and J. Q. Huo contributed equally.
Notes
The authors declare no competing financial interest.
Figure 1. Possible mechanisms of pyrroles formation.
ACKNOWLEDGMENTS
■
The authors acknowledge the National Natural Science
Foundation of China (Nos. 32001927 and 31871981), Youth
Natural Science Foundation of Hebei Province, China (Nos.
B2019204030 and C2020204116), Innovation Team of
Modern Agriculture Industry Technology System of Hebei
Province (Nos. HBCT2018020205), and Hebei Agricultural
University (Nos. 201842 and YJ201963) for financial support.
J.M. thanks the National Natural Science Foundation of China
feedstocks aryl-aldehydes and terminal acetylenes. This
method used easily accessible starting materials and exhibited
broad substrate scope and good functional group tolerance. A
wide variety of 2,3,5-triaryl-1H-pyrroles were obtained in good
to high yields. Because of its potential to generate valuable
building motifs in a single step with tandem C−N and C−C
bond formations, we anticipate this method of N−H-free
pyrrole synthesis will find its applications in medicinal
chemistry. Further studies to elucidate the reaction mechanism
in detail are underway in our laboratories.
(
21801128 and 22071107) and Natural Science Foundation of
Jiangsu Province, China (BK20170965).
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01287.
Detailed experimental procedures, characterization data,
and NMR and HRMS spectra for all products (PDF)
5
2
Accession Codes
CCDC 2069079 contains the supplementary crystallographic
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https://doi.org/10.1021/acs.orglett.1c01287
Org. Lett. 2021, 23, 4348−4352