One-Pot Construction of 1-Phenylchromeno[3,4- b]pyrrol-4(3 H)-one: Application to Total Synthesis of Ningalin B and a Pyrrolocoumarin-Based Electrochromic Switch

Article abstract of DOI:10.1021/acs.orglett.9b01830

An efficient construction of 1-phenylchromeno[3,4-b]pyrrol-4(3H)-one via coupling of 1-styrylpyrrolidine and 4-chloro-3-nitrocoumarin as a key step is reported. This reaction is further applied to the total synthesis of the natural product ningalin B in f

Full text of DOI:10.1021/acs.orglett.9b01830

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
One-Pot Construction of 1‑Phenylchromeno[3,4‑b]pyrrol-4(3H)‑one:
Application to Total Synthesis of Ningalin B and a Pyrrolocoumarin-
Based Electrochromic Switch
Chun-Ku Wu,† Zhiqiang Weng,*,‡ and Ding-Yah Yang*,†
†Department of Chemistry, College of Science, Tunghai University, Taichung 40704, Taiwan
‡State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fujian 350108,
China
S
* Supporting Information
ABSTRACT: An efficient construction of 1-phenylchrom-
eno[3,4-b]pyrrol-4(3H)-one via coupling of 1-styrylpyrroli-
dine and 4-chloro-3-nitrocoumarin as a key step is reported.
This reaction is further applied to the total synthesis of the
natural product ningalin B in five linear steps with an overall
yield of 41.5% and a pyrrolocoumarin-based electrochromic
switch.
he phenyl-substituted pyrrolocoumarin represents a
tion as shown in Scheme 1. Unfortunately, all previous
attempts7 for this coupling reaction failed to give the desired
T
molecular scaffold that is mainly present in the marine
alkaloids lamellarin D1 and ningalin B2 (Figure 1).
Scheme 1. Proposed Retrosynthesis of Phenyl-Substituted
Pyrrolocoumarin 1
product in good yields, presumably due to the fact that 4-
chloro-3-nitrocoumarin is unstable under basic conditions and
is prone to undergo lactone ring opening.8 Here, we describe
the synthesis of 1-phenylchromeno[3,4-b]pyrrol-4(3H)-one
via first coupling of 1-styrylpyrrolidine and 4-chloro-3-nitro-
coumarin under neutral conditions, followed by acid-mediated
reductive cyclization. This methodology is further extended to
the total synthesis of nature product ningalin B and a
pyrrolocoumarin derivative. The latter’s electrochemical
properties are also explored.
Scheme 2 outlines the synthesis of 1-phenylchromeno[3,4-
b]pyrrol-4(3H)-one (1), ningalin B skeleton 5, and diphenyl-
substituted pyrrolocoumarin 12. We initiated our studies by
investigating the coupling of 4-chloro-3-nitrocoumarin (3)
Figure 1. Two phenyl-substituted pyrrolocoumarin-containing natural
products.
Compounds containing phenyl-substituted pyrrolocoumarins
generally exhibit diverse biological activities including
immunomodulatory activity,3 HIV-1 integrase inhibition,4
and cytotoxicity.5 Additionally, some pyrrole-/coumarin-fused
heterocycles have been documented to be susceptible to
oxidation upon UV irradiation and thus may potentially
function as organic redox switches.6 In light of their
pharmacological potential along with the associated intriguing
functional properties, the development of efficient synthesis of
phenyl-substituted pyrrolocoumarins is highly desired. A
simple and efficient route for its preparation would be the
base-mediated coupling of 2-phenylacetaldehyde and 4-chloro-
3-nitrocoumarin, followed by acid-promoted reductive cycliza-
Received: May 26, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01830
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
can actually be prepared in just two synthetic steps from 2-
phenylacetaldehyde (4). Moreover, compound 1 could be
brominated with NBS in THF at 0 °C to yield compound 11.10
The Suzuki coupling of 11 with phenylboronic acid in the
presence of Pd(OAc)2, SPhos, and K2CO3 in dioxane afforded
the diphenyl-substituted pyrrolocoumarin (12) in good yield.11
After realizing the preparation of ningalin B skeleton 5, we
then pursue the total synthesis of ningalin B and its derivative.
Scheme 4 shows the two-step synthesis of the appropriately
Scheme 2. Synthesis of Compounds 1, 5, and 12
Scheme 4. Preparation of 4-Chloro-3-nitrocoumarins 13
and 14
with enamine 7 (prepared in situ by p-TsOH-catalyzed
condensation of 2-phenylacetaldehyde (4) with pyrrolidine
(6)).9 To our delight, simple mixing of 3 and 7 in methylene
chloride at room temperature for 5 min led to the formation of
the desired 3-nitrocoumarin 8 in 92% yield. The subsequent
hydrolysis of 8 in the presence of HCl in acetonitrile gave a
mixture of the keto 9a and enol 9. The latter’s molecular
structure was unambiguously confirmed by X-ray crystal
analysis as depicted in Figure 2. Further reduction of the
substituted 4-chloro-3-nitrocoumarin precursors 13 and 14.
Coumarin 13 was prepared by first nitration of 4-hydroxy-6,7-
dimethoxycoumarin (15) with fuming nitric acid in chloroform
to give 3-nitrocoumarin 16. The subsequent heating of 16 with
POCl3 in DMF afforded the 4-chlorocoumarin 13 in good
yield. Conversely, the 4-chlorocoumarin 14 was prepared the
other way around by first chlorination of 4-hydroxycoumarin
17 with POCl3 in acetonitrile to generate the 4-chlorocoumar-
in 18. The following nitration of 18 with nitric acid in acetic
acid at low temperature furnished the compound 14.
Scheme 5 outlines the preparation of ningalin B (19) from
13. Similar to that of 1, the pyrrolocoumarin 21 was prepared
Scheme 5. Synthesis of Ningalin B
Figure 2. X-ray crystal structures of 9 (left) and 1 (right).
nitro group of the enol 9 to the corresponding amine with iron
power, followed by cyclization and aromatization, afforded the
target compound 1 (Figure 2). Final alkylation of 1 with (2-
bromoethyl)benzene (10) in the presence of K2CO3 as a base
in DMF at 70 °C for 1 h furnished the ningalin B skeleton 5.
To shorten the synthesis, compound 1 can also be prepared in
a one-pot multistep manner via mixing of 3, 4, and 6 in
methylene chloride for 1 h, followed by sequential addition of
acid and iron power without isolation of the enamine 8 and
enol 9 as shown in Scheme 3. Thus, the ningalin B skeleton 5
via mixing of coumarin 13, 2-(3,4-dimethoxyphenyl)-
acetaldehyde (20), and pyrrolidine (6) in methylene chloride
for 1 h, followed by sequential addition of acid and iron power
to yield the tetramethoxy-substituted pyrrolocoumarin 21 in
54% yield. Alkylation of 21 with 4-(2-bromoethyl)-1,2-
dimethoxybenzene (22) in the presence of K2CO3 as a base
in DMF afforded the fully protected ningalin B (23). Final
exhaustive demethylation of 23 with excess of boron
tribromide in methylene chloride at low temperature gave
rise to the target ningalin B (19) in five linear steps with an
overall yield of 41.5% from commercially available coumarin
15.
Scheme 3. One-Pot Multistep Synthesis of Pyrrolocoumarin
1
Scheme 6 depicts the preparation of diphenyl-substituted
pyrrolocoumarin 24 from coumarin 14. Again, the pyrrolo-
coumarin 25 was prepared via mixing of coumarin 14, 2-
B
DOI: 10.1021/acs.orglett.9b01830
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Organic Letters
Letter
functional group on coumarin of 24 decreases the oxidation
potential of the pyrrolocoumarin moiety from 1.14 to 0.76 V.
Further, the CV of 24 showed no substantial changes in the
redox potentials even after being scanned for 40 cycles,
implying that it may potentially possess electrochromic
properties.
Scheme 6. Synthesis of Diphenyl-Substituted
Pyrrolocoumarin 24
Figure 4 depicts the spectroelectrochemical spectra of 24 in
acetonitrile prior to and after the applied external potential. In
phenylacetaldehyde (4), and pyrrolidine (6) in methylene
chloride for 1 h and followed by sequential addition of acid
and iron power to yield the pyrrolocoumarin 25 in 81% yield.
The subsequent bromination of 25 with NBS in THF gave the
brominated 26. Final Suzuki coupling of 26 with phenyl-
boronic acid in the presence of K2CO3 under refluxed
conditions in dioxane afforded the compound 24 in five
steps with an overall yield of 46.5% starting from coumarin 17.
With both compounds 12 and 24 in hand, their potential
functional properties were then evaluated. Figure 3 shows the
Figure 4. (Top) Spectroelectrochemical spectra of 24 in CH3CN (5
× 10−5 M) with 0.1 M TBAPF6 at an applied oxidation potential of
0.55 V (vs Ag/AgCl). (Bottom) Spectroelectrochemical spectra of the
oxidized 24 at an applied reduction potential of 0.20 V (vs Ag/AgCl).
the absence of the external potential, compound 24 was
virtually colorless with absorption maximum wavelength at 353
nm. With the increase of exposure time (0−60 s) to an
oxidation potential of 0.55 V, a new broad absorption band
with the peak wavelength around 515 nm gradually emerged,
along with the appearance of three isosbestic points at 254,
290, and 383 nm. We speculate that the colorless solution
changes to red may be attributed to the formation of an amine
cation radical on the coumarin moiety.12 Conversely, applying
a reduction potential of 0.20 V (vs Ag/AgCl) to the oxidized
24 resulted in the gradual decrease of the absorbance at 515
nm (Figure 4, bottom). The initial UV−vis spectra of 24 were
almost fully recovered, and the solution became colorless again
after 2 min. That is, the absorbance intensity at 515 nm of the
oxidized pyrrolocoumarin 24 can be reversibly modulated by
the external potentials. Thus, a new organic redox switch was
established on the basis of an amino-substituted pyrrolocou-
marin scaffold.
Figure 3. Cyclic voltammogram of 12 (top) and 24 (bottom, 40
cycles) recorded in CH3CN (1 × 10−3 M) containing TBAPF6 (0.1
M) as supporting electrolyte at a scan rate of 100 mV/s.
cyclic voltammogram (CV) of 12 and 24 recorded in
acetonitrile with 0.1 M TBAPF6 supporting electrolyte at a
scan rate of 100 mV/s. An oxidation potential of 1.14 V (vs
Ag/AgCl) was detected for the pyrrolocoumarin moiety of 12.
On the other hand, two one-electron reversible oxidation
waves at +0.40 and +0.76 V corresponding to aminocoumarin
and pyrrolocoumarin moieties were clearly observed for 24.
This observation suggests that incorporation of an amino
In summary, we have demonstrated that the phenyl-
substituted pyrrolocoumarin 1 can be efficiently constructed
via coupling of 1-styrylpyrrolidine and 4-chloro-3-nitro-
C
DOI: 10.1021/acs.orglett.9b01830
Org. Lett. XXXX, XXX, XXX−XXX

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coumarin, followed by sequential hydrolysis, reduction, and
cyclization. This methodology was further extended to the
total synthesis of natural product ningalin B in five linear steps
with an overall yield of 41.5% and diphenyl-substituted
pyrrolocoumarin 24 in five linear steps with an overall yield
of 46.5%. Finally, the cyclic voltammogram and spectroelec-
trochemical studies indicated pyrrolocoumarin 24 exhibits
electrochromic properties.
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.9b01830.
Synthesis of compounds 1, 5, 8, 9, 11−19, 21, and 23−
26 and experimental details (PDF)
Accession Codes
CCDC 1916726, 1917203, 1917205−1917206, and 1917208
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge via www.ccdc.ca-
m.ac.uk/data_request/cif, or by emailing data_request@ccdc.
cam.ac.uk, or by contacting The Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
+44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: yang@thu.edu.tw.
*E-mail: zweng@fzu.edu.cn.
ORCID
Zhiqiang Weng: 0000-0001-6851-1841
Ding-Yah Yang: 0000-0002-3611-2042
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Ministry of Science and Technology of the
Republic of China, Taiwan, for financially supporting this
research under Contract No. MOST 107-2113-M-029-002.
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Org. Lett. XXXX, XXX, XXX−XXX