Copper-catalyzed carbene insertion and ester migration for the synthesis of polysubstituted pyrroles

Article abstract of DOI:10.1039/d0cc04157b

Copper-catalyzed carbene insertion/ester migration/cyclization of enaminones and α-diazo compounds occurred efficiently to afford 2-ester polysubstituted pyrroles under mild conditions in moderate-to-good yields. Substituent functionality was well tolerated and¹³C-labelled experiments demonstrated 1,2-ester migration during the reaction.

Full text of DOI:10.1039/d0cc04157b

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DOI: 10.1039/D0CC04157B
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Copper-catalyzed carbene insertion and ester migration for
synthesis of polysubtituted pyrroles†
Mingrui Li,a Yiming Sun,a Yuxing Xie,b Yang Yu,c Fei Huang,*ab and He Huang*ab
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Copper–catalyzed carbene insertion/ester migration/cyclization
of enaminones and α-diazo compounds occurred efficiently,
affording 2-ester polysubstituted pyrroles under mild conditions
in moderate to good yields. Substituents functionality are well
tolerated and 13C-labelled experiments demonstrated 1,2-ester
migration during the reaction.
pyrrole backbone.
Diazo compounds are ideal reaction substrates in
diverse organic synthesis, including C-H insertion, X-H
insertion, C-C insertion, cyclopropanation of alkenes,
and Wolff rearrangement.8 Among them, transition
metal catalyzed C-C or C=C insertion reaction of diazo
compounds is attractive for construction of two new
C-C bonds.9 In our previous work,10 we reported
copper-catalyzed formal carbene migratory insertion
into the olefinic C=C bonds of α-oxo ketene
N,S-acetals with hydrazines (Scheme 1a). Then we
wondered whether diazo compounds could be applied
to carbene migratory insertion reactions into C=C
bond of readily available enaminones to generate N-
heterocyclic products. To our delight, the unexpected
2-ester polysubstituted pyrrole and 1,4-ketoaldehyde
intermediate were obtained when using Cu(OTf)2 as
the catalyst with diazo compounds and enaminones.
Pyrroles1 are an important class of N-heterocycle
compounds which are widely present in various
natural products and drugs molecules. Especially, 2-
ester polysubstituted pyrrole motif2-3 shows many
biological activities for treating some diseases (Fig. 1).
In view of the potential drug applications, the
development of more efficient catalytic strategies for
synthesis of 2-ester pyrrole core is of great
significance in organic chemistry and medicinal
chemistry. To date, various methods were reported to
synthesize pyrroles,4 but only a limited number of
processes have been known for the preparation of 2-
ester polysubstituted pyrroles.5 The classical method
for synthesis of 2-ester polysubstituted pyrrole ring is
Paal-Knorr reaction, dehydration of 1,4-dicarbonyl
compound with a primary amine under acidic
conditions.6
Then
some
cycloaddition
and
condensation reactions,7 including [4+1], [3+2], and
[2+2+1], has been developed to construct a 2-ester
Fig. 1 Selected examples of biological active molecules containing
a pyrrole scaffold.
Recently, Jin and co-workers11 reported a similar
work (Scheme 1b). But they used AgOTf as catalyst
through a different pathway with 1,4-iminone as
reaction intermediate. Herein, more economical
Cu(OTf)2 was used as the catalyst to synthesis of 2-
1
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ester polysubstituted pyrrole via 1,2-ester migration
of 1,4-ketoaldehyde intermediate.
However, the replacement of benzyl group to methyl
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in R1 deteriorated the yield of prodDuOctI: 140t.1t0o394/D00%CC. 04157B
Scheme 2 Scope of enaminones 1. Reaction conditions: 1 (0.5
mmol), 2 (0.6 mmol), Cu(OTf)2 (0.05 mmol), DCE (5 mL), 60 oC, 4 h,
0.1 MPa air. Isolated yields are given.
Scheme
reactions.
1
2-ester polysubstituted pyrrole formation
The reaction was initially investigated with
enaminone 1a and methyl 2-diazo-2-phenylacetate 2a
as the model substrates to screen the reaction
conditions (Table S1). After screening catalysts,
solvents, temperature and additives, the cyclization
reaction conditions were optimized to 10 mol%
Cu(OTf)2 as the catalyst, DCE as the solvent at 60 °C,
1a and 2a in a 1.0:1.2 molar ratio and reacting under
an air atmosphere in 64% isolate yield (Table S1, entry
4). Under the optimized reaction conditions, the scope
of enaminones 1 was then explored by reacting them
with 2a as the substrate (Scheme 2). Substituents such
as methoxyl, fluoro, chloro, bromo on the aryl moiety
of benzylamino (NCH2Ar) functionality were tolerated,
efficiently giving the desired products 4b-g in 50-55%
yields. Formation of o-, m-, p-OMe-substituted
products 4b-4d (52-55%) showed that no obvious
steric effects on the yield of the reaction. Variation of
the amino group in enaminones 1 to phenethyl-,
ethyl-, propyl-, allyl and phenylamino afforded 4h-4l in
30-66% yields. Electron-donating group p-Me and
electron-withdrawing group p-Br on the NAr
functionality led to the desired products 4m (62%) and
4n (23%), exhibiting obvious electronic effects. In
addition, bulky 2-napthyl- or primary amine NH2-
based enaminones 1o-1p could react with 2a to
generate the corresponding products 4o-4p.
Substituent halogen atoms such as 4-F, 4-Cl, and 4-Br
on the aryl group of R1 did not obvious affect the
formation of the desired products 4q-4s (61-62%).
Then, the generality of α-diazo esters 2 was
investigated (Scheme 3). Other esters 2 such as ethyl,
allyl, and benzyl ester variants were compatible,
forming the products (4u-4w) in moderate to good
yields (50-67%). α-Diazo esters 2 with both electron-
donating and -withdrawing substituents on the
aromatic ring in R3, such as methyl, fluoro, chloro,
bromo, and iodo, were well tolerated for this process
(4x-4z2, 49-55%) without remarkable electronic effect.
However, the strongly electron-withdrawing group
trifluoromethyl moiety on the aryl group diminished
the formation of 4z3 (39%). To our delight, the
bulkiness of -OTs group on the aryl group did not
deteriorate the reaction efficiency in the synthesis of
4z4 in 62% yield. Ethyl 2-diazoacetate (2l) could be
transformed into the target products 4Z5. It should be
noted that when 1s was reacted with 2h in short time
(3 min), the 1,4-ketoaldehyde intermediate 3z1 was
obtained in 59% yield. The molecular structures of
compounds 3z1 and 4a were further confirmed by the
X-ray single crystal crystallographic analysis (Fig.S3-4).
To demonstrate the potential applicability of our
synthetic
approach,
gram-scale
preparation
experiment and derivation of pyrrole product were
conducted (Scheme 4). Under the standard
conditions, the target products 4a was efficiently
generated in 62% yield by the reaction of 1a with 2a
from the 5 mmol scale preparation. Halogenation12 of
4a were carried out using HBr and NCS as
halogenation agents, giving 4-bromo pyrrole 5 and 4-
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chloro pyrrole 6 in 97% and 58% yield, respectively.
With LiAlH4 as the reductant,13 2-ester pyrrole 4a was
readily reduced to 2-hydroxymethyl pyrrole 7 in
excellent yield (89%). In presence of NaOH,14 the
corresponding product 8 was hydrolyzed in 86% yield,
which is a useful intermediate to get the antitumor
compound in drug synthesis15 These transformations
indicate that our method is alternative strategy to
access pyrrole derivatives.
under standard conditions, but compoundVi3ewaArrteiclaecOtnelinde
with enaminone 1a to form the target product 4a in
30% yield. These results indicated that 1,4-
ketoaldehyde 3 was intermediate in this cyclization
reaction.
DOI: 10.1039/D0CC04157B
Scheme 5 Control experiments.
In order to gain insights into the reaction
mechanism, some control experiments were carried
out (Scheme 5). Addition of a radical scavenger
TEMPO or BHT to the reaction mixture slightly
reduced the yield of 4u, suggesting not involvement of
a radical pathway (see SI for details). Under dry DCE
conditions, the reaction of enaminone 1a with 2a did
not occur, whereas addition of 1.0 equiv of water as
the additive, the reaction exhibited a reactivity similar
to that in the undried DCE (Table S1, entry 4, 64%),
giving the corresponding product 4a in 65% yield.
Then, in the presence of dry DCE with 1 equiv of
H218O, reacting enaminone 1s with of α-diazo ester 2g
in 3 min formed the target 18O-labelled 1,4-
ketoaldehyde intermediate 3z1[18O] in 57% yield.
These results revealed that water was required in this
cascade cyclization reaction and the formyl oxygen in
intermediate 3 was originated from water. Under the
standard condition, enaminone 1a reacted with the
13C-labelled substrate α-diazo ester 2b[13C] to afford
the corresponding 13C-labelled pyrrole product
4u[13C], which was unambiguously identified by the
13C{1H} NMR and HMBC (1H detected heteronuclear
multiple bond correlation) analysis, suggesting ester
migration during the reaction (eq 2 and see SI for
details). Based on these experiment results and
previous literature,16-18 we proposed a plausible
carbene insertion/1,2-ester migration/ cyclization
mechanism (Scheme S1).
Scheme 3 Scope of α-diazo esters 2. Reaction conditions: 1 (0.5
mmol), 2 (0.6 mmol), Cu(OTf)2 (0.05 mmol), DCE (5 mL), 60 oC, 4 h,
0.1 MPa air. Isolated yields are given.
Scheme 4 Gram-scale reaction and functionalization of methyl 1-
benzyl-3,5-diphenyl-1H-pyrrole-2-carboxylate.
Due to the continuous detection of compound 3
during the cascade cyclization reaction, we
hypothesized that
3
would be the reaction
intermediate. Then the relationship between
compound 3, product 4 and reaction time was studied
particularly by GC-MS (Fig. S1). Moreover, the reaction
of compound 3a with benzylamine did not occur
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Y. Liu, J. Org. Chem., 2010, 75, 510; (h) S. Ngwerume and J.
E. Camp, Chem. Commun., 2011, 47,D1O8I:5170;.1(0j3)V9iWe/wD.0ABCrt.iCclL0ei4Ou1n,5li7HnBe.
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In summary, we have developed a concise and
mild copper(II)-catalyzed carbene insertion/ester
migration/cyclization protocol of enaminone with α-
diazo compounds for the synthesis of polysubstituted
pyrroles. The gram-scale preparation experiment and
synthesis of highly functionalized pyrroles derivation
demonstrate the potential applicability of our
synthetic method.
We are grateful to the National Natural Science
Foundation of China (21901124), Jiangsu university
natural science research program (19KJB150032,
19KJB610013).
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Conflicts of interest
There are no conflicts to declare.
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R2
DOI: 10.1039/D0CC04157B
O
HN
R4
R1
O
O
O
O
1
R2
10 mol% Cu(OTf)2
- NHR2
O
N
+
R3
R1
R3
N2
1
O
R4
O
R1
R3
R4
intermediate 3
4
O
2
A mild synthetic protocol to access 2-ester pyrroles through Cu(OTf)2catalysed
carbene insertion/ester migration/cyclization of enaminones and α-diazo compounds
was reported.