Transition-metal-free and facile synthesis of 3-alkynylpyrrole-2,4-dicarboxylates from methylene isocyanides and propiolaldehyde

Article abstract of DOI:10.1039/d1nj03596g

A transition-metal-free, facile and efficient method for the synthesis of 3-alkynylpyrrole-2,4-dicarboxylates from methylene isocyanides and propiolaldehyde with moderate to good yields has been developed. The direct transformation process and good tolerance of various substituents make it an alternative approach to previous protocols, and potential applications of these investigated compounds are expected with or without post-modifications.

Full text of DOI:10.1039/d1nj03596g

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Transition-metal-free and facile synthesis of 3-alkynylpyrrole-2, 4-
dicarboxylates from methylene isocyanides and propiolaldehyde
†
†
Xiaoli Huoa, b, , Xiaojuan Chena, , Liya Yua, Chong Zhanga, b, Linghui Zenga, b, Huajian Zhua, b, Jiaan
Received 00th January 20xx,
Accepted 00th January 20xx
Shaoa, b, *, Liping Fuc, *, Jiankang Zhanga, b, *
DOI: 10.1039/x0xx00000x
A
transition-metal-free, facile and efficient method for the reported methods rely on the incorporation of alkynyl groups
synthesis of 3-alkynylpyrrole-2, 4-dicarboxylates from methylene into N-protected and activated positions of pyrroles, and the
isocyanides and propiolaldehyde with moderate to good yields has regioselectivity greatly depends on the substrate structure.
been developed. The direct transformation process and good Therefore, direct assembly of alkynylated pyrroles together
tolerance to various substituents make it an alternative approach with other functional groups from readily available starting
to previous protocols, and potential applications of these materials has gained particular momentum in recent years. To
investigated compounds are expected with or without post- explore more convenient protocols, Wan31 and Jiang32
modifications.
independently reported Cu-catalyzed reactions of terminal
alkynes with 2H-azirines and vinyl azides to construct
alkynylated pyrroles (Scheme 1, Eq b). Additionally, various
Pyrroles have been explored and exploited as one of the most
prevalent and significant heterocycles in pharmaceutical and
material sciences1-6. To date, dozens of therapeutic compounds
constructed with this N-containing five-membered scaffold
have been approved for clinical use, including Atorvastatin and
Sunitinib7-9, while functionalization of pyrroles may pave new
avenues to the exploration of these valuable structures. Alkynes
are among the most ubiquitous and versatile functional groups,
which not only bring in rigidity property of the overall molecule
but also introduce possibilities for construction of macrocycles
with post-modifications10-14. Integrating the advantages of both
segments, alkynylpyrrole-containing compounds have been
validated with antifungal, antihepatitis and dopamine 4 agonist
cascade cross-coupling/cyclization/(alkynylation) strategies
were employed from (di)yne with “N=C-C” or “N-C=C” motifs
(Scheme
1
, Eq c)33-38. However, in most of these cases,
drawbacks with respect to the substrate scope and precious or
transition-metal catalysis (Au, Ag, Ru, Pd, Ni) still existed. Thus,
it is of great significance to develop versatile methods that
accomplish facile access of alkynylpyrroles from readily
available and simple starting materials.
Methylene isocyanides are versatile building blocks in
constructing cycles including pyrrole39-42. Actually, the reaction
between isocyanides with alkynone to furnish pyrroles was
reported (Scheme 1, Eq d), however, it was the triple bond
activities15-17
.
contributed in assembling the cycle but not the carbonyl group.
Besides, alkynylated pyrroles could also be afforded from
methylene isocyanides and ene-yne-ketones, although they
were only by products43. In this context, we envisioned the
possibility of regioselective reaction of isocyanides with alkynals,
in which carbonyl group was involved in the cyclization while
triple bond was retained. We herein describe an elegant
method providing 3-alkynylpyrrole-2, 4-dicarboxylates via
cyclization of methylene isocyanides and propiolaldehydes
Recently, a variety of approaches have been established for the
synthesis of alkynylated pyrroles, most of which greatly rely on
the use of transition-metal catalysis. Sonogashira cross-coupling
is the most general method with reaction of halogenated
pyrroles with terminal alkynes in the presence of Pd/Cu
synergistic catalyst (Scheme
1
, Eq a)18-22. An alternative
, Eq
approach is named inverse-Sonogashira coupling (Scheme
1
a), which requires electronically activated pyrroles or directing
groups to assist the C-H activation process23-28. Notably, a more
recent direct alkynylation strategy has emerged as an efficient
tool, Nevado29 developed an Au (I)-catalyzed ethynylation of N-
benzyl pyrroles with electron-deficient terminal alkynes, while
Yu30 documented a Cu (II)-promoted ortho alkynylation of N-
methyl pyrroles with various terminal alkynes. However, the
under basic conditions (Scheme
We embarked on the investigation by exploring the reaction of
3-phenylpropiolaldehyde (1a) with ethyl isocyanoacetate (2a
(Table ). Initially, various bases were screened to identify the
1).
)
1
optimized condition, which were proved to be an essential
influence factor for entry into the desired product 3a. The
results revealed that most of the attempted organic and
inorganic bases were not beneficial for the reaction, with yields
less than 30% (entries 1-4), while product 3a could be obtained
in 64% yield only in the presence of DBU (entry 5), which was
a.
School of medicine, Zhejiang University City College.
b.College of Pharmaceutical Sciences, Zhejiang University.
c. Department of Pharmacy, Shaoxing Hospital of Traditional Chinese Medicine.
† These authors contributed equally.
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verified as the optimal one. To our delight, the reaction could
be finished within 5 min, and the yield even decreased after 3 h
reaction (entries 5 and 6). Subsequently, diverse solvents were
attempted, and most ones were proved to be doable with yields
ranging from 30%-80% (entries 6-11). In these cases, acetone
was indicated to be the most suitable one, furnishing product
3a in 75% yield (entry 6), while almost no product was observed
with alcohol as solvent. Additionally, either increasing or
decreasing the equivalency of DBU did affect the yield (entries
12-15). 0.5 equiv. of DBU led to a yield of 63% (entry 12), while
even lower yield was observed when raised to 5-fold (entry 15).
These results indicated that the product might be not that
stable in the presence of high concentration of DBU. Besides, by
diminishing the amount of 2a to 2 equiv. (entry 16), the
outcome dropped to 56%; for this reason we kept the ratio
1/2.5 between 1a and 2a for our studies. We also investigated
Table
1
. Optimization of the reaction condiVtiieownAsraticle Online
DOI: 10.1039/D1NJ03596G
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Temp
(℃)
Entry
Base/equiv.
Solvent
Yieldb/%
1c
2c
3c
4c
5c
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NaH/1.5
NaOH/1.5
K2CO3/1.5
Et3N/1.5
DBU/1.5
DBU/1.5
DBU/1.5
DBU/1.5
DBU/1.5
DBU/1.5
DBU/1.5
DBU/0.5
DBU/1.0
DBU/2.0
DBU/5.0
DBU/1.5
DBU/1.5
DBU/1.5
DBU/1.5
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
DCM
ACN
Toluene
DCE
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trace
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72
70
o
the effect on temperature: decreasing the temperature to 0 C
o
and -20 C gave lower yields of 72 % and 59% (entries 17 and
18), respectively, certainly due to the slower reaction velocity,
and when we increased the temperature to room temperature
THF
o
(25 C, entry 19), the yield was also slightly diminished, giving
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
rise to the desired product in a 70% yield, thus the temperature
of 10 oC were retained as the optimal one.
-20
0
25
aReaction conditions unless otherwise specified: 0.5 mmol of 1a
1.25mmol of 2a, 5 mL of solvent, 5 min, air; bIsolated yield; cReacted for
3h; d2 equiv. of 2a
,
With the established conditions in hand, the scope of substrate
propiolaldehyde
phenylpropiolaldehyde (1a) with an unsubstituted phenyl ring
participated well in this transformation, electron-withdrawing
groups at the para-position on the phenyl ring seemed
unfavorable for promoting the reaction, furnishing the
1 was investigated (Scheme 2). While the 3-
corresponding target compounds (3b-3i) in moderate to good
yields, and electron-donating groups at the same position could
be tolerated (3j and 3k). Besides, substitutions at the ortho and
meta positions on the phenyl ring were uninfluential for the
reaction, analogues 3l
reaction of 1p which bears a sterically demanding naphthyl
group with 2a 3p was obtained in a good yield of 74%. Notably,
both heterocyclic (1q) and aliphatic (1r) propiolaldehydes
reacted well with 2a to afford the corresponding alkynylpyrroles
3q and 3r in 40% and 48% yields, respectively.
Subsequently, with the aim to evaluate the endurance of
various methylene isocyanides, different isocyanoacetates with
-3o were obtained in 65-71% yields. In the
,
Scheme 1. Approaches to alkynylated pyrroles
diverse
phenylpropiolaldehyde 1a under the standard parameters
(Scheme ). Generally, all the reactions proceeded smoothly to
ester
moieties
were
reacted
with
3-
3
generate corresponding products (3s-3v) in moderate to good
yields.
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The practicability of the present cyclization was further
evaluated by gram-scale syntheses of prDoOdIu: 1c0t.130a39(/SDc1hNeJ0m3e5946G).
When 5 mmol scale of 3-phenylpropiolaldehyde 1a was treated
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with 12.5 mmol of ethyl isocyanoacetate 2a
83% yield, which was even higher than 0.5 mmol scale reaction.
Additionally, post-modification of 3a with 2-
iodotrifluoroacetanilide afforded pyrrolo[1,2-a]-quinoxaline
in 31% yield (Scheme ), which was an important precursor of
, 3a was obtained in
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validated platelet aggregation inhibitor41 and believed to
exhibit various biological activities after screening.
On the basis of above results, a plausible mechanism is
proposed in Scheme
5. We envisaged that methylene
isocyanide was deprotonated in the presence of DBU to
generate 2a’. Then, a nucleophilic addition between 2a’ and
propiolaldehyde took place to produce the intermediate I,
which was further attacked by second molecule of active
isocyanide and dehydrated to generate II. Subsequently,
deprotonation of intermediate II followed by intra-molecular
cyclization afforded IV. Finally, elimination of hydrogen cyanide
produced intermediate V41, which upon interconversion formed
Scheme
otherwise specified: 0.5 mmol of
5 mL of solvent, 10oC, air. Isolated yield.
2
. Scope of the propiolaldehydes. Reaction conditions unless
the final product 3a
.
1
, 1.25mmol of 2a, 1.5 equiv. of DBU,
Scheme
unless otherwise specified: 0.5 mmol of
DBU, 5 mL of solvent, 10oC, air. Isolated yield.
3
. Scope of the methylene isocyanides. Reaction conditions
1
, 1.25mmol of 2a, 1.5 equiv. of
Scheme 5. Plausible reaction mechanism
Conclusions
In summary, we have developed a powerful and wide-in-scope
strategy for the synthesis of 3-alkynylpyrrole-2, 4-
dicarboxylates with simple and readily accessible starting
materials. The facile approach occurs in the presence of DBU
and is transition-metal-free, which would be utilized in
synthetic chemistry. Besides, the functionalized pyrroles are
anticipated with biological activities and potentials for further
post-synthetic modifications.
Scheme 4. Gram-scale synthesis and synthetic application of product 3a
Conflicts of interest
This journal is © The Royal Society of Chemistry 20xx
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23 J.P. Brand, J. Charpentier and J. Waser, Angew. Chem. Int.
There are no conflicts to declare.
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Edit., 2009, 48, 9346-9349.
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25 E. Brachet and P. Bemont, J. Org. Chem., 2015, 80, 7519-
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27 X. W. Li, G. C. Wu, X. H. Liu, Z. Z. Zhu, Y. P. Huo and H. F.
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Acknowledgements
The authors are grateful for the financial support from the
National Natural Science Foundation of China (81803432),
Medical and Health Projects of Shaoxing Science and
Technology Bureau (2018C30115), Medical Health Science and
Technology Project of Zhejiang Provincial Health Commission
(2019RC085), Agricultural and Social Development Fund of
Hangzhou Science and Technology Committee (20201203B150
and 20201203B148), Research Project on Application of Public
Welfare Technology supported by Science Technology
Department of Zhejiang Province (LGF20H30003) and The
Second Round of Excellent Innovation Team of Hangzhou
M u n i c i p a l U n i v e r s i t y i n 2 0 1 9 f o r L . - H . Z e n g .
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