Synthesis of 2-Formylpyrroles from Pyridinium Iodide Salts

Article abstract of DOI:10.1021/acs.orglett.0c02178

The first I2-mediated synthesis of 2-formylpyrroles from pyridinium salts is reported. This protocol enables the synthesis of diversely substituted 2-formylpyrroles in good yields under operationally simple conditions. The detailed mechanistic studies reveal that the reaction proceeds via a novel H2O-triggered ring opening of the pyridinium salt and a subsequent intramolecularly nucleophilic addition sequence.

Full text of DOI:10.1021/acs.orglett.0c02178

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Letter
Synthesis of 2‑Formylpyrroles from Pyridinium Iodide Salts
Ke Xu, Wenjing Li, Rui Sun, Lihua Luo, Xue Chen, Chunchun Zhang, Xueli Zheng, Maolin Yuan,
Haiyan Fu,* Ruixiang Li, and Hua Chen
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ABSTRACT: The first I2-mediated synthesis of 2-formylpyrroles from pyridinium
salts is reported. This protocol enables the synthesis of diversely substituted 2-
formylpyrroles in good yields under operationally simple conditions. The detailed
mechanistic studies reveal that the reaction proceeds via a novel H2O-triggered ring
opening of the pyridinium salt and a subsequent intramolecularly nucleophilic
addition sequence.
discovery of a more efficient and greener route to synthesize 2-
formylpyrroles is still highly desirable.
2-Formylpyrrole-derived alkaloids are one of the most
important classes of structural motifs found in numerous
pharmaceutical molecules,1 natural products,2 and functional
materials.3 In addition, they also represent privileged building
blocks and have been widely used as intermediates in the
construction of porphyrins,4 anion receptors in biomedical
analysis,5 unnatural base pairs,6 and oligopyrrole-based metal-
locomplexes.7
Pyridines are cheap and abundantly available and have
served as versatile synthetic intermediates in organic
chemistry.20 2-Formylpyrrole formation by the rearrangement
of the pyridine N-oxides via photolysis21 has been known.
Unfortunately, the yield of this process is very low. We are
interested in developing the synthetic method for 2-
formylpyrrole from pyridinium salts. In the past several
decades, molecular I2 has been widely used in promoting the
intramolecular cyclization to prepare many important hetero-
cycles, such as furans, thiophenes, and pyrroles.22 In view of
the capability of iodine in promoting intramolecular cyclization
and the ring-opening tendency of the pyridinium salts in the
presence of an appropriate nucleophile,23 we expected that the
treatment of the pyridinium salt with a basic aqueous solution
in the presence of I2 would lead to a H2O-triggered ring-
opening reaction to form an acyclic intermediate, which
subsequently undergoes an intramolecularly nucleophilic attack
to give 2-formylpyrroles. To the best of our knowledge, this
type of transformation has never been reported in the
literature.
To evaluate the feasibility of the proposed protocol, a variety
of I2 sources, bases, solvents, and additives were extensively
screened (Table S1). The optimal condition was determined
to be the following: N-methyl-2-phenylpyridinium salts A
(0.25 mmol) were treated with 0.64 equiv of I2 in the presence
of 4.0 equiv of K2CO3 and 1 equiv of methyl methacrylate
(MMA) in a solvent mixture of DCE/H2O (1:1) at 80 °C
under air for 20 h. (See Table S1 for details.) The desired 2-
Given its broad applicability, many synthetic methods
toward 2-formylpyrroles have been developed (Scheme 1).
So far, numerous efficient methodologies have been developed
for the synthesis of 2-formylpyrroles. The conventional
methods rely on the Vilsmeier−Haack formylation of the
preformed parent pyrrole,8 which is usually synthesized by
Hantzsch,9 Knorr,10 Paal−Knorr,11 Barton−Zard,12 and
Trofimov reactions.13 A sustainable Maillard approach to 2-
formylpyrroles from primary amines and sugar was described
by Fujimaki, Zhao, Koo, and others.14 Padwa and coworkers
constructed the 6-phenyl-2-formylpyrrole from 2H-azirine by
treating with Grubb’s catalyst.15 A highly substituted 2-
formylpyrrole was successfully synthesized by Sato and
Urabe by using a coupling reaction of acetylene and nitrile
mediated by a titanium reagent.16 A two-step synthesis from
ketones and 4-formyloxazole was also described by Sen-
anayake.17 In 2017, Kumar’s group reported a pseudo-[3 + 2]
annulation between N-(4-methoxyphenyl)aldimines and gluta-
raldehyde for the direct synthesis of pyrrole-2,4-dialdehydes.18
Very recently, Wu et al. prepared the 2-formylpyrroles bearing
an ester group at the three-position from methyl ketones,
arylamines, and acetoacetate esters with the assistance of
molecular iodine.19
Received: July 1, 2020
However, these methods suffer from several drawbacks, such
as the use of a toxic reagent, the restricted availability of
substrates, the requirement for specially designed starting
molecules, tedious experimental operations, poor functional
group compatibility, and harsh conditions. Therefore, the
https://dx.doi.org/10.1021/acs.orglett.0c02178
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
a
Scheme 1. Represent Examples for 2-Formylpyrrole
Synthesis
Table 1. Optimization of Reaction Conditions
b
entry
variation from standard conditions
yield (%)
1
2
3
4
none
79
72
68
56
0
NBS instead of I2
NCS instead of I2
r.t.
5
w/o I2
6
7
8
9
10
11
12
13
14
w/o K2CO3
2.0 equiv of K2CO3
w/o MMA
H2O
0
55
68
54
0
48
56
74
70
DCE
DCE/H2O 10:1
DCE/H2O 4:1
DCE/H2O 3:2
DCE/H2O 2:3
a
Reaction conditions: A (0.25 mmol), I2 (0.64 equiv), K2CO3 (4
equiv), MMA (1 equiv), DCE/H2O (1:1, 0.25 M), 80 °C, 20 h.
b
Isolate yields.
(THF), were screened as cosolvents, and DCE proved to be
the best one (Table S1). Using H2O alone as the solvent
resulted in a 54% yield of 1, and in the absence of H2O, no
product was formed (Table 1, entries 9 and 10). The variation
of the ratio of DCE/H2O from 1:1 decreased the yield to
different extents (Table 1, entries 11−14).
With the optimal condition in hand, we next investigated the
scope of the pyridinium salts (Scheme 2). Several features
should be pointed out: (1) In the case of aryl-substituted
pyridinium salts, a wide range of functional groups on the aryl
rings were tolerated. The pyridinium salts bearing either the
electron-withdrawing (p-F, p-Cl, p-CF3, p-CN) or -donating
(p-Me, p-MeO) substitutents on the 2-aryl group underwent
the reaction very well to afford the corresponding 2-
formylpyrrole derivatives 1−7 in 62−84% isolated yields. (2)
Notably, N-methylpyridinium salts with heteroaryl groups such
as furanyl, thiophenyl, and pyridinyl, could also be employed,
giving products 9−11 in 50−78% yields. (3) In the case of
alkyl-substituted pyridinium salts, the reaction outcome was
dependent on the types of the alkyl groups. The pyridinium
salts bearing an α-branched alkyl group at their two-position
reacted very well to deliver the desired products 12−16 in 66−
86% yields, whereas the linear alkyl-substituted substrate led to
a very low yield of the product. On the contrary, the 2-
cyclohexyl- and 2-cyclopropylpyridinium salts could be
smoothly converted into the 5-cycloalkyl-2-formylpyrroles 17
and 18 in 69 and 28% yields, respectively. (4) It is worth
mentioning that the reaction efficiency was greatly influenced
by the substitution patterns of the pyridinium ring. For
example, the 3-aryl-substituted pyridinium salts generally
produced the corresponding products 19−23 in moderate
yields (40−56%). The 2,3-disubstituted pyridinium salts were
also viable substrates, furnishing the products 24−29 in 48−
74% yield. (5) Introducing the functional groups such as MeO,
CN, or NO2 on the pyridinium ring resulted in a complicated
mixture. For instance, 3-methoxy-1-methyl-2-phenylpyridi-
nium iodide only afforded product 30 in a very low yield of
18%. (6) The alkyl group on the quaternary nitrogen also
formylpyrrole could be obtained in 79% isolated yield, with
21% of pyridinium salt recovery, which was determined on the
basis of the H NMR analysis of the crude reaction mixture
1
(Table 1, entry 1). It should be pointed out that the optimal
amount of I2 is 0.64 equiv, which seems insufficient to react
with pyridinium salt (1.0 equiv), but the resulting I− or the
counterion I− of the pyridinium salt would be oxidized by air
to iodine. Notably, the replacement of I2 with N-
bromosuccinimide (NBS) or N-chlorosuccinimide (NCS)
also produced the product in comparable yield (72 and 68%
yield, respectively) (Table 1, entries 2 and 3). The reaction
could still occur at room temperature and afforded the product
in 56% yield (Table 1, entry 4). The controlled experiments
showed that no product was formed in the absence of I2 or
K2CO3, revealing their important roles in the reaction (Table
1, entries 5 and 6). Of the examined bases, K3PO4 provided a
similar result as K2CO3, and other bases, such as Na2CO3,
Li2CO3, Cs2CO3, KOAc, NaOH, KtOBu, and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) (Table S1), were all
inferior in the reaction. The amount of K2CO3 also had an
impact on the reactivity. The yield of 1 decreased to 55% when
the amount of K2CO3 was decreased from 4 to 2 equiv (Table
1, entry 7). The removal of the additive MMA from the system
impaired the reaction efficiency to some extent and generated
1 in 68% yield (Table 1, entry 8). The use of other olefins as
the additives exhibited a lower efficiency than MMA (Table
S1). Finally, various solvents, including 1,2 dichloroethane
(DCE), CCl4, acetone, PhCl, hexane, and tetrahydrofuran
B
https://dx.doi.org/10.1021/acs.orglett.0c02178
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a b
,
scavenger,2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), the
2-formylpyrrole was still obtained in 78% yield, without any
loss of activity (Table S1, entry 45). This indicated that the
free-radical pathway might be ruled out. Isotope labeling
experiments by reacting A in H218O−DCE solution led to the
formation of [18O]-1 exclusively (Scheme 4a), and this result
Scheme 2. Scope of Substrates
Scheme 4. Studies on the Reaction Pathway
was unambiguously confirmed by mass spectrometry (Figure
S2). This provided direct evidence of the fact that the O atom
originates from the solvent H2O. In addition, the model
reaction conducted in D2O afforded 1 without deuterium
incorporation in CHO group (Scheme 4b). Meanwhile, A-d1
completely delivered the product with deuterium incorpo-
ration into CHO; these results implied that the hydrogen in
the −CHO group came from C6−H instead of H2O (Scheme
4c).
Furthermore, a competitive reaction of A and A-d1 under the
standard condition demonstrated a moderate inverse secon-
dary kinetic isotope effect (SKIE) of 0.85. As the previously
described experiments proved, the H in the CHO group of the
product originated from the C6−H bond of the 2-phenyl-
pyridinium salts. Because both of the carbons to which the H
atom attached are sp2-hybridized and an inverse SKIE value
was observed for the C6−H bond, we assume that the C6 goes
through rehybridization from sp2 to sp3 and then to sp2.
Furthermore, the sp2 to sp3 rehybridization must occur during
the rate-determining step, and thus an inverse secondary KIE
was expected (KH/kD ≅ 0.85) (Scheme 4d).24
As previously mentioned, when NBS or NCS was used as
the additive instead of I2, the reaction could also produce the
desired products in comparable yields (Table 1, entries 2 and
3). This might be attributed to I2 generated in situ via the
oxidation of an iodide anion with NBS or NCS. To further
confirm this assumption, we reacted the pyridinium salts A′
bearing CF3COO− as the counteranion with NBS or NCS and
found that the substrates were totally recovered without any
product 1 (Scheme 4e). Whereas A′ reacts in the presence of
I2, a 76% yield of product 1 was obtained (Scheme 4f). These
results strongly suggest the vital role of I2 in the process.
a
All reactions were run under the conditions: A (0.25 mmol), I2 (0.64
equiv), K2CO3 (4 equiv), MMA (1 equiv), DCE/H2O (1:1, 0.25 M),
80 °C, 20 h. Isolate yields.
b
influences the reaction reactivity. The reactivity gradually
decreased with increasing alkyl chain length (31−33), and N-
benzyl-2-phenylpyridinium iodide gave the product 34 in 43%
yield. (7) N-methyl-isoquinolinium iodide afforded 3-phenyl-
1-formylisoindole 35, albeit in a relatively lower yield of 29%.
(8) However, the N-methyl iodide salts of quinoline, 1,10-
phenanthroline, 2,2′-bipyridine, terpyridine (III−VI), proved
to be not effective substrates in this reaction.
The protocol was next demonstrated in a scale-up reaction.
Thus the reaction of 10 mmol A under the standard conditions
afforded the 2-formylpyrrole derivative 1 in 66% yield. The
CHO could be easily transformed into the functionalities such
as ester, amide, carbonitrile, and methyl groups (Scheme 3).
To shed light on the mechanistic pathway, a set of
experiments was carried out. When the reaction was conducted
in the presence of a stoichiometric amount of radical
Scheme 3. Scale-Up Synthesis of 1 and Its Applications
C
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Letter
A plausible reaction pathway proposed on the basis of
experimental observations is depicted in Scheme 5. The
Xueli Zheng − Key Laboratory of Green Chemistry &
Technology, Ministry of Education College of Chemistry,
Sichuan University, Chengdu 610064, P. R. China;
orcid.org/0000-0001-8394-0310
Scheme 5. Plausible Reaction Pathway
Maolin Yuan − Key Laboratory of Green Chemistry &
Technology, Ministry of Education College of Chemistry,
Sichuan University, Chengdu 610064, P. R. China
Ruixiang Li − Key Laboratory of Green Chemistry &
Technology, Ministry of Education College of Chemistry,
Sichuan University, Chengdu 610064, P. R. China;
orcid.org/0000-0003-0756-3722
Hua Chen − Key Laboratory of Green Chemistry & Technology,
Ministry of Education College of Chemistry, Sichuan University,
Chengdu 610064, P. R. China; orcid.org/0000-0003-4248-
8019
reaction was initiated by nucleophilic attack on the C6 position
of the pyridinium salts A by H2O to give species B. One
molecule of HI was released with the assistance of a base, and
in the presence of molecular iodine, a hemiaminal species C
containing a three-membered iodonium ring was formed,
which exists in equilibrium with the iodonium enamine
aldehyde D. The intramolecular cyclization of D followed by
the elimination of HI through intermediate E gives the final
product N-methyl-5-phenyl-2-formylpyrrole. The role of MMA
in the reaction remains unclear in this stage.
In conclusion, we have developed an efficient way to
synthesize 2-formylpyrroles from cheap and readily available
pyridinium salts. The reaction proceeds as an I2-mediated,
H2O-triggered pyridinium ring-opening/intramolecular cycli-
zation sequence. Further exploration of the construction of
other types of heterocycles from pyridinium salts is ongoing.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02178
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(nos. 21871187 and 21572137), the Collaborative Fund of
Luzhou Municipal Government and Sichuan University
(2018CDLZ-13), and the Key Program of Sichuan Science
and Technology Project (2019YFG0146) for financial support.
We also thank Chunchun Zhang from the Centre of Testing &
Analysis, Sichuan University for NMR measurements.
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02178.
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AUTHOR INFORMATION
Corresponding Author
■
Haiyan Fu − Key Laboratory of Green Chemistry & Technology,
Ministry of Education College of Chemistry, Sichuan University,
Chengdu 610064, P. R. China; orcid.org/0000-0002-7185-
2062; Email: scufhy@scu.edu.cn
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Authors
Ke Xu − Key Laboratory of Green Chemistry & Technology,
Ministry of Education College of Chemistry, Sichuan University,
Chengdu 610064, P. R. China
Wenjing Li − Key Laboratory of Green Chemistry &
Technology, Ministry of Education College of Chemistry,
Sichuan University, Chengdu 610064, P. R. China
Rui Sun − Key Laboratory of Green Chemistry & Technology,
Ministry of Education College of Chemistry, Sichuan University,
Chengdu 610064, P. R. China
Lihua Luo − Key Laboratory of Green Chemistry & Technology,
Ministry of Education College of Chemistry, Sichuan University,
Chengdu 610064, P. R. China
Xue Chen − Key Laboratory of Green Chemistry & Technology,
Ministry of Education College of Chemistry, Sichuan University,
Chengdu 610064, P. R. China
Chunchun Zhang − Analytical & Testing Center, Sichuan
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