Ring-contraction of hantzsch esters and their derivatives to pyrrolesviaelectrochemical extrusion of ethyl acetate out of aromatic rings

Article abstract of DOI:10.1039/d1gc00487e

Electrochemical ring-contraction of HEs and theirs pyridine derivatives is developed to obtain polysubstituted pyrroles. This process provides an orthogonal utilization of Hantzsch esters for the well-documented application as side chain or hydrogen donors. The formal transformation shows an extrusion of ethyl acetate out of the pyridine ring in a single step. In addition to the novel transformation, we also discovered the Lewis acid's intermolecular control of regioselectivity during an intramolecular electrochemical process. The reaction provides a number of polysubstituted pyrroles that have never been accessed, including pharmaceutical intermediates and photoswitches. An unusual 4-electron continuous reduction drives the unprecedented anionic dearomatization/ring-contraction/rearomatization pathway.

Full text of DOI:10.1039/d1gc00487e

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Ring-contraction of hantzsch esters and their
derivatives to pyrroles via electrochemical
extrusion of ethyl acetate out of aromatic rings†
a,b,c
Cite this: Green Chem., 2021, 23,
3468
Xu Liu,‡a Chang Liu‡b and Xu Cheng
*
Electrochemical ring-contraction of HEs and theirs pyridine derivatives is developed to obtain polysubsti-
tuted pyrroles. This process provides an orthogonal utilization of Hantzsch esters for the well-documen-
ted application as side chain or hydrogen donors. The formal transformation shows an extrusion of ethyl
acetate out of the pyridine ring in a single step. In addition to the novel transformation, we also discovered
the Lewis acid’s intermolecular control of regioselectivity during an intramolecular electrochemical
process. The reaction provides a number of polysubstituted pyrroles that have never been accessed,
including pharmaceutical intermediates and photoswitches. An unusual 4-electron continuous reduction
drives the unprecedented anionic dearomatization/ring-contraction/rearomatization pathway.
Received 7th February 2021,
Accepted 8th April 2021
DOI: 10.1039/d1gc00487e
rsc.li/greenchem
sis and Lewis acid catalysis.5 In addition, they have been uti-
lized as hydrogen atom donors in various catalytic radical reac-
Introduction
Pyrroles are five-membered nitrogen heterocycles with intrin- tions.6 Recently, 4-substituted HEs have emerged as highly
sic hydrogen bonding ability.1 Their electronic and steric pro- reactive radical donors in Lewis acid catalysis,7 photoredox cat-
perties can be regulated by the introduction of multiple substi- alysis,8 thermal radical reactions,9 and electrochemical reac-
tuents onto their carbon skeletons, and tetra- and penta-sub- tions.10 In all these innovative transformations, only one sub-
stituted pyrrole moieties are present in molecular photo- stituent on the HE, either a hydrogen or an alkyl group, ends
switches2 and numerous pharmaceuticals (Fig. 1).3 The estab- up in the target molecule; the aromatized pyridine ester bypro-
lished methods for pyrrole synthesis involve condensation duct is separated and then discarded (Scheme 1a).11 However,
reactions, but the synthesis of pyrroles with multiple different in terms of atom economy and functional group diversity, the
types of functional groups poses a challenge and requires pyridine core structure would be ideal for the construction of
careful selection of the substrates and condensation con- heterocyclic compounds. Along these lines, we speculated that
ditions.4 Therefore, a versatile, modular method for polysubsti- ring-contraction reactions of HE-derived pyridine derivatives
tuted pyrrole synthesis that would allow full modification of could provide a new strategy for accessing polysubstituted pyr-
the carbon skeleton would be highly desirable.
roles. However, this strategy presents two challenges. First,
We speculated that Hantzsch esters (HEs) might be useful because of the electron deficiency of the HE pyridine ring, the
for this purpose. HEs are polysubstituted heterocycles that can ester groups are stable under various conditions, and there-
be prepared by modular, multicomponent condensation reac- fore, activation of these groups and the subsequent ring con-
tions. HEs are widely used as hydride donors in organocataly- traction would necessitate a tremendous driving force. Second,
pyrroles tend to be more reactive than pyridines. In a pioneer-
aInstitute of Chemistry and Biomedical Sciences, Jiangsu Key Laboratory of Advanced
Organic Materials, National Demonstration Center for Experimental Chemistry
Education, School of Chemistry and Chemical Engineering, Nanjing University,
Nanjing, 210023, China. E-mail: chengxu@nju.edu.cn
bState Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin,
300071, China
cState Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology,
Zhejiang University of Technology, Hangzhou, 310032, China
†Electronic supplementary information (ESI) available. CCDC 2052648. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
d1gc00487e
Fig. 1 Polysubstituted-pyrrole-containing
photoswitches
and
‡These authors contribute equally to this work.
pharmaceuticals.
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Table 1 Optimization of conditions for ring contraction of HE-derived
pyridine 1aa
Entry Electrolyte
Lewis acid (equiv.) Solvent Yieldb (%)
1
LiClO4
LiClO4
LiClO4
BF3·Et2O (3)
—
THF
THF
THF
THF
THF
THF
MeCN
26
0
0
0
35
0
Trace
2
3c
4d
5
BF3·Et2O (3)
BF3·Et2O (5)
BF3·Et2O (3)
Zn(OTf)2 (3)
BF3·Et2O (3)
BF3·Et2O (3)
BF3·Et2O (3)
BF3·Et2O (5)
BF3·Et2O (5)
—
nBu4NBF4
nBu4NBF4
nBu4NBF4
nBu4NBF4
nBu4NBF4
nBu4NBF4
nBu4NBF4
nBu4NBF4
hv 254 nm, MeOH
6
7
8
9
10
11f
12
MeOH Trace
DMF
THF
THF
—
15
90e (75)
0
Scheme 1 Utilization of 2H-pyridines as radical donors and pyrrole
precursors.
0 (12% HE)
a Reaction conditions, unless otherwise noted: 1a (0.2 mmol), electro-
lyte (0.1 mmol), Lewis acid, H2O (40 equiv.), solvent (5 mL), Zn(+)/GF
(−), 20 mA, rt, 12 h. b Yields were determined by gas chromatography.
c No H2O. d No electricity. e Isolated yield. f GF(+)/GF(−).
ing study, the Kellogg group reported a protocol for the dearo-
matization of pyridine diesters under UV irradiation, which
gave rise to dihydropyridines as major products via a bis-
radical pathway (Scheme 1b).12 In this report, only one
example showed pyrrole as the minor product, providing a clue
for both the possibility and the challenge of the proposed ring-
contraction transformation.
cathode, LiClO4 as a supporting electrolyte, a Lewis acid
(BF3·Et2O) as a promoter, and water as the hydrogen source. To
our delight, these conditions afforded pyrrole 2a in 26% yield
by gas chromatography (entry 1). In the absence of the Lewis
acid, water, or electricity (entries 2–4), the conversion of 1a
failed to proceed. Using n-Bu4NBF4 instead of LiClO4 boosted
the yield slightly (to 35%, entry 5), whereas there was no reac-
tion when Zn(OTf)2 was employed as the Lewis acid promoter
(entry 6). Several solvents that are widely applied in electro-
chemical synthesis showed inferior results (entries 7–9).
However, we found that increasing the amount of BF3·Et2O to
5 equiv. dramatically improved the yield to 90% by gas chrom-
atography and 75% isolated yield (entry 10). None of the
desired product was obtained when the Zn anode was replaced
with inert graphite felt (entry 11), suggesting that the Zn
anode was essential to prevent the oxidation of 2a in this undi-
vided cell configuration. Finally, using the de-aromatization
protocol reported by Kellogg, UV irradiation of 1a afforded the
corresponding HE (2H-1a) in 12% isolated yield, and pyrrole
2a was not detected (entry 12). A reaction at a concentration of
1.6 mol L−1 could afford a faradaic efficiency of 59% (ESI,
section 2.1†).
Given the need for a strong driving force, we envisioned
that an electrochemical process would be a good option as
electrochemical methods have been successfully used for
various types of transformations.13 Specifically, we speculated
that a cathode reduction might lead to a new pathway invol-
ving an anion intermediate instead of a bis-radical species.
This speculation was supported by a number of previously
reported cathodic reduction reactions. For example, the Baran
group developed an electrochemical Birch reduction chemistry
that involves rapid electron transfer to arenes and gives rise to
unsaturated carbocycles.14 In addition, activation of various
functional groups, including CO2,15 unsaturated C–C bonds,16
aryl–CN bonds,17 C–halogen bonds,18 chlorosilane,19
nitrones,20 nitroarenes,21 diazo compounds,22 and ketones,23
by means of innovative cathodic reduction chemistry have
been demonstrated recently. Despite of these achievements,
however, the dearomative cleavages of C–C/CvC bonds and re-
aromatization cascade reaction still remain elusive to known
protocols (Scheme 1c). Herein, we report the first example of
ester abstraction from pyridines via such electrochemical
reduction reaction.
Having optimized the conditions (Table 1, entry 9), we
extended the reductive ring-contraction reaction to additional
pyridines 1 (Scheme 2). Pyrroles 2b–2l, which bear phenyl
groups with various substitution patterns, were obtained in
42–76% yields; functionality such as a thioether group, an
aniline ring, a bromine atom, and a borate group were well tol-
Results and discussion
To explore the reaction conditions, we chose pyridine deriva- erated. Dihydrobenzofuryl-substituted pyrrole 2m was syn-
tive 1a as the model substrate (Table 1). First, we carried out thesized in 61% yield, and thienyl-substituted pyrrole 2n could
an electrochemical reaction (20 mA) in THF in an undivided be obtained as well, although the yield was only 43% owing in
cell with Zn as a sacrificial anode, graphite felt (GF) as the part to the formation of its corresponding dihydropyridine
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Next we determined whether our method could be used to
obtain pyrroles with four different substituents from unsym-
metrical pyridine substrates, which requires that the regio-
selectivity of the ring-contraction step be controlled
(Scheme 3). To our delight, the reaction of 1ah under the stan-
dard conditions afforded pyrrole 2ah, which has four different
substituents on the ring, in 53% yield. Next we evaluated the
effects of various R groups. We found that a free hydroxyl
group (2ai, 41%), an O-silyl group (2aj, 48%), an imidate (2ak,
38%), a Boc-protected amide (2al, 40%), and an estrone (2am,
44%) all survived the reduction conditions and had little effect
on the reaction yields. The regioselectivity was confirmed by
X-ray analysis of a crystal of 3,24 which was derived from
pyrrole 2ai. The method was also compatible with a primary
alkyl bromide (2an, 42%). In contrast, the difluoroamide
group of 2ao decreased the product yield because of the strong
affinity of the group for silica gel, which was used during puri-
fication. The product 2ap, which has a pyrazole group, was
obtained in 47% isolated yield.
To elucidate the reaction mechanism, we carried out a
series of experiments under controlled conditions. First, cyclic
voltammetry analysis showed that in aqueous THF, BF3·Et2O
substantially decreased the barrier to the anodic reduction of
1b (by 0.7 V, Scheme 4a). In addition, a square wave voltamme-
try experiment indicated that multiple electron transfers were
involved in the reduction (Scheme 4b). Comparison of the 11B
NMR spectrum of aqueous BF3 with the spectra of aqueous
Scheme 2 Synthesis of polysubstituted pyrroles by ring contraction of
pyridines derived from symmetrical HEs. Conditions: 1 (0.2 mmol), elec-
trolyte (0.1 mmol), BF3 etherate (1 mmol), H2O (8 mmol), solvent (5 mL),
Zn(+)/GF(−), 20 mA, rt, 12 h.
2H-1n. A pyrrole with a bulky α-naphthenyl group (2o) was pro-
duced in 69% yield. We also screened pyridine substrates
derived from alkyl-substituted HEs. We were pleased to find
that pyrrole 2p could be synthesized in 79% yield by our
method; in contrast, in the only previously reported syn-
thesis,12 which was achieved by UV irradiation, the yield of
this compound was only 16%. Alkyl-substituted pyrroles 2p–
2w were prepared in moderate yields, and furyl (2x) and dialkyl
thioether (2y) groups remained intact under the reaction con-
ditions. Products 2z–2ab, which have bulkier secondary alkyl
groups, were obtained in similar yields. We also evaluated the
effect of the steric bulk of the ester groups and found that
larger esters showed slightly diminished yields (compare the
yields of 2ac–2ae). Pyrroles 2af and 2ag, which have long
carbon chains instead of a methyl group, were also accessible
(57% and 53%, respectively).
Scheme 3 Synthesis of polysubstituted pyrroles by ring contraction of
pyridines derived from unsymmetrical HEs. Conditions: 1 (0.2 mmol),
electrolyte (0.1 mmol), BF3 etherate (1 mmol), H2O (8 mmol), solvent
(5 mL), Zn(+)/GF(−), 20 mA, rt, 12 h.
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Scheme 5 Plausible pathway for anionic ring-contraction reactions
involving four-electron cathodic reduction.
protonation by water-BF3, an electron is transferred from the
graphite felt cathode to pyridine 1 to generate radical B.
Transfer of a second electron from the cathode forms anionic
intermediate C. At this stage, steric repulsion between com-
plexed BF3 and the adjacent alkyl groups distorts the ester
group on the side of the molecule with the larger alkyl group;
this distortion leads in turn to greater disruption of the conju-
gation between the ester and the double bond in the ring.
Therefore, intramolecular Michael addition of the carbanion
occurs selectively at the less hindered side of the nitrogen
atom and is followed by a second protonation to afford bicyclic
species D. Opening of the cyclopropane ring of D generates a
five-membered-ring structure E, which has an imine group.
Next a third electron transfer from the cathode takes place,
coupled with a third protonation, giving rise to radical
F. Finally, the cleavage of a C–C bond, transfer of a fourth elec-
Scheme 4 Analysis of reactants and control experiments.
mixtures of BF3 and 1b or 2H-1b revealed that the pyridine did tron, and protonation furnish pyrrole 2 and ethyl acetate. In
not bind strongly to BF3, whereas 2H-1b interacted strongly this sequence, the water could provide protons for the acti-
with BF3 (Scheme 4c). If BF3·Et2O was replaced with trifluoroa- vation of pyridine and formation of acetate.
cetic acid (a protonic acid), the reaction gave a 3.9 : 1 mixture
Subsequently, we attempted to achieve direct electro-chemi-
of pyrroles 2ah and 2ah′ in a combined yield of 49% cal conversion of a HE to a pyrrole in one pot (Scheme 6a).
(Scheme 4d). This result suggests that BF3 played an important When we used graphite felt for both the anode and the
role at the ring-contraction stage. Because a reaction of pyri- cathode, dehydrogenative oxidation of HE 2H-1b in THF con-
dine 1aq gave both dihydropyridine 2H-1aq and pyrrole 2aq as taining nBuNBF4 gave pyridine intermediate 1b, which then
products, we used this substrate to elucidate the intermediate underwent the ring-contraction reaction when we switched to
in the transformation. Specifically, when the reaction of 1aq a zinc anode and added BF3·Et2O and water to the reaction
was carried out in THF-d8, no deuterium was found in either mixture. This one-pot procedure provided 2b in 59% yield over
2aq, 2H-1aq, or benzyl acetate 4 (Scheme 4e). In addition, in a two steps. The ring-contraction reaction could also be carried
reaction of 1aq in THF containing D2O, benzyl acetate d3-4 was out on a 15 g scale to generate 2b with no loss in yield relative
isolated as the major product by means of gas chromato- to that obtained from the submillimolar-scale reaction
graphy–mass spectrometry and NMR analysis. The outcomes (Scheme 6b). Furthermore, pyrrole 2q was used to prepare a
of both of these labelling experiments suggest that the hydro- modified photoswitch 6 in 18% yield, which is comparable to
gen source was not THF but water.
the reported yield of trimethyl pyrrole azobenzene
On the basis of the above-described results, we propose the (Scheme 6c).2 This result suggests that our method could
reaction pathway shown in Scheme 5. First, coupled with the provide a substrate pool for the development of photoswitch-
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Author contributions
Xu Liu and Chang Liu contributed equally to this work.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by the National Science Foundation
of China (no. 22031008, 22071105), the QingLan Project of
Jiangsu Education Department, the National Key Research and
Development Program of China (2019YFC0408300), and the
State Key Laboratory Breeding Base of Green Chemistry-
Synthesis Technology (Zhejiang University of Technology,
Hangzhou 310032).
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In summary, we have developed a method for the first time for
the electrochemical preparation of polysubstituted pyrroles
from HE-derived pyridines. This method, which is unique as it
involves four electron transfers, is complementary to the estab-
lished applications of HEs. More than 40 pyrroles with a
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